IMMUNOLOGY FLASH CARDS

1. Variolation
2. Who introduced vaccination?
3. Who is the father of microbiology?
4. Who introduced antiseptic techniques for surgery?
5. When were antibiotics developed?
6. When were antibiotics commercialized?

1. Injection of crusted material from smallpox blisters used to “immunize” in ~16th century
2. Jenner – for smallpox in England, late 1700s
§ Inoculated cowpox (“vaca” Latin for cow)
3. Pasteur (1860s)
§ Showed bacteria could be killed by heat
§ Developed chicken cholera, anthrax, and rabies vaccines
4. Lister
5. 1920s
6. 1940s

1. Antigen

2. Immunogen

3. Hapten

4. Tolerogen

5. Epitope

1. Chemical foreign to host which induces immune response

· Reacts w/antibodies
2. Induces an immune response (does not necessarily react w/antibodies) – ex. bovine serum
albumin (BSA)
3. Antigen that alone does NOT induce immune response
· Eg penicillin, dinitrophenyl (DNP)
· Not immunogenic b/c they cannot activate helper T cells (can’t bind to MHC proteins)
· They can stimulate a response when covalently bound to a “carrier” protein (such as BSA)
4. Antigen altered to induce tolerance (no immune response)
5. An antigenic determinant (confers specificity for Ab)

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1. Defensins

2. Acute phase proteins

1. Proteins secreted by phagocytes

· Have antimicrobial effects

2. Produced mainly by liver

· Similar to defensins
· Bind to microbes, making them more susceptible to being destroyed
· Ex. C-reactive protein, mannose-binding protein

Innate (nonspecific) immunity

§ Protects against microbes in general

§ Classified into 3 major categories:
o Physical barriers (skin, mucous membranes)
§ Fatty acids secreted by sweat glands have antibacterial and antifungal activity
o Phagocytic cells (neutrophils, macrophages, NKs)
o Proteins (complement, lysozyme, interferon)
§ Requires complement, cytokines and leukocyte

Give examples of how reduced phagocytosis predisposes people to infection

1. _ Infections in children w/defects in phagocytic process

§ Chronic granulomatous disease: NADPH oxidase defect à can’t generate H2O2 à can’t kill
bacteria
§ Chediak-Higashi syndrome: abnormal lysosomal granules cannot fuse w/phagosome
2. Frequent infections occur in pts w/PMN counts <500/mL
§ Usually result of immunosuppressiv drugs, irradiation
3. Splenectomy, which removes imp source of phagocytes and immunoglobulins (Igs),
predisposes to sepsis
a. Streptococcus pneumoniae à causes ~50% of episodes of sepsis in splenectomized pts

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Acquired (adaptive/specific) immunity

§ Protects against a particular microbe

§ Requires lymphocytes and antibodies
§ Gets more intense w/each antigen exposure, therefore displaying immune memory
§ Results either from:
o Exposure to the organism (active immunity) OR
o Receipt of preformed antibody made in another host (passive immunity)
§ MEMORY response is the adaptive immunity response
o This is controlled by lymphocytes
o Lymphocytes are very specific in their antigen recognition and response

Passive acquired immunity

§ Temporary protection against an organism

§ Acquired by receiving serum containing Abs from another person or animal (i.e. you don’t
make the Abs)
§ Transplacental
o Thru placenta (IgG)
o Thru breast milk (IgA)
§ Serum therapy
o Ex. infusion of serum w/Abs upon hepatitis exposure
§ Advantage: protective abilities are present immediately, whereas active immunity has delay
§ Disadvantage: [Ab] _ fast à protection lasts 1-2 months

Active acquired immunity

§ Protection based on exposure to organism

§ Slower onset but longer duration than passive immunity
§ Advantage: anamnestic (2ndary) response occurs
§ Abs protect against organisms by:
o Toxin neutralization, lysis of bacteria in presence of complement, opsonization (helps
phagocytosis)
§ T cells mediate variety of rxns including:
o Destruction of virus-infected cells and bacteria, macrophage activation, delayed
hypersensitivity
§ Convalescence à exposed to Ag, then “more” immune
§ Vaccine à administration of antigens

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Diseases and abnormalities that predispose to infections

1. Diabetes
§ Often have S aureus infections, perhaps b/c:
o Extensive atherosclerosis (causes tissue anoxia)
o Defect in neutrophil function
2. Sickle cell anemia
§ Often have Salmonella osteomyelitis
3. Pts w/certain congenital cardiac defects
· Predisposed to endocarditis caused by streptococci
· Neutrophils have difficulty penetrating vegetations formed on valves in endocarditis
4. Pts w/an anortic aneurysm
§ Prone to vascular infections by Salmonella species

Two components of the acquired (adaptive) immune system

1. Cell-mediated immunity
§ Consists primarily of killer T cells
§ Utilizes lymphocytes, cytokines, phagocytes
§ Inhibits organisms (fungi, parasites, and certain intracellular bacteria)
§ Kills virus-infected cells and tumor cells
2. Antibody-mediated (humoral) immunity
§ Consists primarily of B cells (and plasma cells)
§ Utilizes antibodies and complement
§ Neutralizes toxins and viruses
§ Opsonizes bacteria (makes them easier to phagocytize)

What bridges the two arms (cell-mediated and humoral immunity) of acquired immunity?

§ Macrophages and certain other phagocytic cells such as dendritic cells

o Participate in both the innate and acquired arms
o As part of innate arm à ingest and kill microbes
o As part of acquired arm à present antigen to helper T cells (essential 1st step in activation of
acquired arm)
§ Note: neutrophils (which are phagocytes have excellent microbicidal abilities) DO NOT
present antigen to helper T cells and therefore function in innate BUT NOT acquired immunity

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RAG

· Recombinase activating gene

· Helps in the formation of lymphocyte receptors
· Part of a family of genes that evolved allowing adaptive immunity
· After these genes evolved, lymphocytes became major player in immunity

Antigen recognition

1. Cognitive (recognition) phase

· Lymphocyte recognizes a foreign antigen by means of a receptor
2. Activation phase
· Proliferation and differentiation of lymphocytes – expression of new genes, acquire new
functions
3. Effector (response) phase
· Effector lymphocytes – newly functioning, eliminate antigen
· Some lymphocytes differentiate into memory cells

Steps in cell-mediated immunity: Bacterial infection

1. Macrophage ingests microbe (eg M tuberculosis)

2. Fragments of microbe – antigens or epitopes – appear on surface of macrophage in association
w/MHC II proteins
3. Antigen-class II MHC protein complex interacts w/antigen-specific receptor on helper T cell
4. Helper T cell is activated and proliferates as result of IL-1 (produced by macrophages) and IL-
2 (produced by lymphocytes)
5. Activated helper T cells, w/activated macrophages, mediate delayed hypersensitivity rxn
specifically against M tuberculosis

Steps in cell-mediated immunity: Viral infection

1. Virus is inhaled and infects cell of respiratory tract

2. Viral glycoproteins appear on surface of infected cell in association w/class I MHC proteins
3. Cytotoxic T cell binds to viral antigen-class I MHC complex à stimulates T cell to grow into a
clone of cells by IL-2 (produced by helper T cells)
4. These cytotoxic T cells specifically kill influenze virus-infected cells by:
· Recognizing viral antigen-class I MHC protein complexes on cell surface
· Releasing perforins that destroy membrane of infected cell

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Steps in antibody-mediated immunity

1. Involves cooperation of macrophages, TH cells, & B cells

2. After processing by macrophage, fragments of antigen appear on its surface in association
w/class II MHC proteins
3. Antigen-class II MHC protein complex binds to specific receptors on helper T cell (TCR = T
cell receptor)
· T cell produces IL-2, IL-4, and IL-5
4. These factors activate B cell
· B cell proliferates & differentiates à plasma cell à Igs
5. Specificity of response is provided by:
· Antigen receptor (TCR) on T cells
· Antigen receptor (IgM) on B cells
· Note: interleukins are not specific

What two important functions do B cells perform during induction process?

1. They recognize antigens w/their surface IgM that acts as an antigen receptor
2. They present epitopes to TH cells in association w/class II MHC proteins
3. Note:
· IgM antigen receptor on B cell can recognize foreign proteins, carbs, lipids, DNA, RNA, etc.
· Class II MHC proteins of B cell can only present peptide fragments to TH cells

Soluble mediators of immunity

1. Acute phase proteins

· Induced by stress (infection, injury)
· Participate in inflammation and healing
· Ex. C-reactive protein, serum amyloid
2. Complement
· Activated by immune complexes
· Participate in immune regulation
3. Cytokines
· Produced by all cells in body
4. Antibodies
· Bind antigen to form immune complex
· Five classes: IgM, IgA, IgG, IgE, and IgD

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Clonal Selection

1. Antigen “selects” a B cell endowed w/the preexisting capacity to make the specific antibody
for that antigen
2. Each person has a large pool of B cells
3. Each B cell bears specific receptor (either IgM or IgD) that can react with 1 antigen (or closely
related group of Ags)
4. An antigen interacts w/B cell w/best “fit” Ig surface receptor
· Stimulates B cells to proliferate and form clone of cells
· Selected B cells à plasma cells à Ig specific for Ag
5. Clonal selection also occurs with T cells
· Antigen interacts w/specific receptor on a Th or Tc cell
· This “selects” cell à expands into clone of cells with the same specificity

Consequences of immune activation

1. Inflammation
· Innate immunity, influx of factors and cells, PMNs
2. Phagocytosis
· Ingestion of particles by macrophages and neutrophils
3. Neutralization
· Ab combines w/antigen and inactivates it
4. Cytotoxic reaction
· Killer cells interact w/target cell and kill it

Origin of immune cells

1. In post-natal life, stem cells reside in bone marrow

2. T cells mature into immunocompetent cells in thymus
· Stem cells lack antigen receptors CD3, CD4, and CD8
· First differentiate to express both CD4 and CD8
· If contacts cell w/class II MHC proteins à CD4+ cell
· If contacts cell w/class I MHC proteins à CD8+ cell

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Thymic education

Two processes that occur in thymus à

1. CD4+ and CD8+ cells bearing antigen receptors for “self” proteins are killed (clonal deletion)
by apoptosis
· Removal of these self-reactive cells = negative selection
· Results in self tolerance (prevents autoimmune rxns)
2. CD4+ and CD8+ cells bearing antigen receptors that do not react w/self MHC proteins are
killed
· Results in positive selection for T cells that react well w/self MHC proteins
· These 2 processes produce T cells selected for their ability to react both w/foreign antigens and
with self MHC proteins

MHC proteins

· “Major histocompatibility complex”

· Perform 2 essential functions in immune response:
o Positive selection of T cells in thymus
o Presentation of antigens to T cells, the initial step required to activate those cells
· Most imp antigens recognized in graft rejection process

GALT

· “gut-associated lymphoid tissue”

· Up to 40% of T cells develop here rather than thymus
· These intraepithelial lymphocytes are thought to provide protection against intestinal pathogens
o Their antigen receptors and surface proteins are different from those of thymus-derived T cells
o Cannot substitute for thymus-derived lymphocytes
§ Evidence: pts w/DiGeorge’s syndrome (lack a thymus) are profoundly immunodeficient

Sepsis

· The presence of pathogenic organisms, or their toxins, in the blood or tissues

· I.e. blood infection that causes disease/symptoms
· Ex. may have bacteremia but no symptoms, thus NOT septic

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Hematopoiesis

1. Blood cells are short lived and are thus continuously renewed from pluripotent stem cells in
bone marrow
· Pluripotent à under influence of cytokines, stem cells become a variety of other cells
· Exception: memory cells, progeny of which last for yrs
2. Process is controlled by cytokines
· IL-7 à imp for B cell development
· IL-3 à acts on early bone marrow progenitor cells
3. GM-CSF - stimulates cells of granulocytic & macrophage
4. M-CSF (macrophage colony stimulating factor)
5. G-CSF (granulocyte colony stimulating factor)
· Used clinically _ speeds up bone marrow recovery

T lymphocytes: Subtypes and Markers

· Subtypes:
o TCR a/b or g/d
o Th-1 – T helper cell
o Th-2 – T helper cell
o Tc – T cytotoxic cell
o Ts – T suppressor cell
o NK – natural killer (large granular lymphocyte)
· Surface markers (CD = cluster designation)
o All T cells à TCR, CD3 (TCR complex)
o Th cells à CD4
o Tc cells à CD8
o NK cells à receptors for class I MHC, CD16

TCR complex

· Formed by 2 portions (TCR + CD3), totaling 7 proteins

o TCR complex: ab-gden
· TCR portion, a/b or g/d, binds the antigen
· Rest of the proteins is the CD3 portion
o CD3 transfers signal across membrane into T cell
· T cells with g/d TCR primarily located in mucosa
o CD8+ (cytotoxic T cells) only
o Limited antigenic repertoire (100 – 1000 clones)
· T cells with a/b TCR are found in the blood
o ~108 different clones
o CD4+, CD8+, or suppressor T cells
o MHC restricted

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1. Th cells
2. Tc cells
3. Ts cells
4. NK cells

1. Two types distinguished by cytokines they secrete:

· Th1: produces IL-2 and IFN
o Involved in cell-mediated immunity
· Th2: produces IL-4 and IL-10
o Involved in humoral immunity
3. TCR, CD8
· Bind to targets and release killer molecules
4. CD4 and CD8
· Release suppressor cytokines
5. CD16 (NO TCR)
· Ag receptor less defined

Which cells express MHC class I? MHC class II?

Which cells do MHC classes present to?

· All nucleated cells express MHC class I

· Only APCs express MHC class II (as well as class I)
o Langherans cells (in skin)
o Interdigitating cells
o Macrophage
o Follicular dendritic cells
o B cells
· Antigens must be presented to T cells by an APC
· MHC I cells present antigen to CD8+ cells
· MHC II cells present antigen to CD4+ cells

Helper T cell produces cytokines. Name them and their function.

1. IL-4 and IL-5

· Help B cells produce Abs
2. IL-2
· Activates CD4 and CD8 cells
3. IFNg
· Actives macrophages (the main mediators of delayed hypersensitivity against intracellular
organisms such as M. tuberculosis)

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What enzymes are involved in the signal transduced by CD3, CD4, and CD8?

1. CD3
· One of its transmembrane proteins – the zeta chain – is linked to a tyrosine kinase called fyn
2. CD4 and CD8
· May signal via tyrosine kinase lck

Function of CD4 lymphocytes

1. Th-2 cells
· Help B cells develop into Ab-producing plasma cells by producing IL-4 and IL-5 (influence
humoral immunity)
2. Th-1 cells
· Help CD8 T cells to become activated cytotoxic T cells by producing IL-2, activate NK cells
· Help macrophages effect delayed hypersensitivity (eg, limit infection by M tuberculosis) by
producing primarily IL-2 and gamma IFN (i.e. activate macrophages)
· Also activate NK cells
· Thus influence CMI

What is the main thing that regulates the balance between Th-1 and Th-2 cells?

· IL-2 levels
o Produced by macrophages
o Increases the number of Th-1 cells
o Thus enhances:
§ Host defenses against organisms controlled by delayed hypersens response
§ Cell-mediated immunity
· Gamma IFN
o Inhibits production of Th-2 cells

1. Cleaved viral peptides associate w/which MHC class?

2. Which MHC class do all other antigens associate with?

1. Class I
a. Viral peptides associate w/class I MHC protein
b. Complex is transported to surface, where viral antigen is presented to receptor on CD8+ cell
2. Class II
a. Foreign protein is cleaved into peptides that associate w/class II MHC proteins
b. Complex is transported to surface of APC, where antigen, in association w/class II MHC
protein, is presented to receptor on CD4+ helper cell
Remember the rule of eight:
CD4 cells interact w/class II, CD8 cells interact w/class I

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Activation of T cells

1. Requires that they recognize a complex on surface of APCs consisting of both the antigen and
a class II MHC protein
2. 1st step à antigen interacts w/TCR specific for that antigen
· CD4 on Th cell also interacts w/class II MHC protein
· Other proteins also help stabilize contact between T cell & APC (LFA-1 on T cell binds to
ICAM-1 on APCs)
3. For full activation of Th cells, costimulator is required à B7 protein on APC must interact
w/CD28 protein on Th cell
· If costimulatory signal occurs: IL-2 is made by Th cell à Th cell capable of performing all of its
functions
· If costimulatory signal does not occur: state of unresponsiveness called anergy ensues

“Accessory events” in T cell activation

1. Receptors imp in adhesive events

· LFA-1 (leukocyte functional antigens)
à Located on CD4 expressing helper T cells
à Interacts with ICAM-1 (intercellular adhesion molecule) on APC
· LFA-3
à Located on class I MHC expressing target cell
à Interacts with CD2 on the CD8 expressing Tc cell
2. Zeta chain, along with CD3 molecule, also important
· Enhances activation process
· Noncovalently interacts w/TCR and MHC complex with CD4 on helper T cells or CD8 on
cytotoxic T cells

CTLA-4

· Protein that appears on the T cell surface after the T cell has been activated
· Binds to B7 by displacing CD28
· Interaction of B7 with CTLA-4 inhibits T cell activation by blocking IL-2 synthesis
o This restores activated T cell to a quiescent state and thus plays an imp role in T cell
homeostasis
· Mutant T cells that lack CTLA-4 participate w/increased frequency in autoimmune rxns
· Administration of CTLA-4 reduces the rejection of organ transplants in experimental animals

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What to T cells recognize?

1. Polypeptide antigens ONLY

2. Furthermore, they recognize those polypeptides ONLY when they are presented in association
w/MHC proteins
3. Th cells recognize antigen associated w/class II MHC protein
4. Tc cells recognize antigen associated w/class I MHC proteins
· This is called MHC restriction: the 2 types of T cells are “restricted” b/c they are able to
recognize antigen ONLY when antigen is presented w/the proper class of MHC protein

Class I MHC proteins

· Generally present endogenously synthesized antigens (eg. Viral proteins)

o Proteins are cleaved by a proteosome
o Peptide fragments associate w/a “TAP” transporter that transports the fragment into the rER
where it associates w/the class I MHC
o Complex of peptide fragment and class I MHC protein then migrates via Golgi to cell surface
· Killed viral vaccines do not activate Tc cells b/c virus does not replicate w/in cells and therefore
viral epitopes are not presented in association with class I MHC proteins

Class II MHC proteins

1. Present the antigens of extracellular microorganisms that have been phagocytized (eg.
Bacterial proteins)
· Extracellularly acquired proteins are cleaved to peptide fragments within an endosome, where
the fragment associates w/class II MHC proteins
· This complex then migrates to the cell surface
2. An “invariant chain” is attached to the class II MHC proteins when they are outside of the
endosome
· Chain degraded by proteases w/in endosome, allowing peptide to attach to class II MHC w/in
compartment
· Prevents endogenously synthesized proteins from associating w/class II MHC proteins

How do B cells interact with antigens?

· Unlike T cells, they interact directly with antigens via their surface antigen receptors (IgM and
IgD)
o Antigens do NOT have to be presented to B cells in association w/class II MHC proteins
· IgM and IgD recognize many different types of molecules, such as peptides, polysaccharides,
nucleic acids, small chemicals (penicillin)

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Describe the events that occur when the antigen-MHC complex on the APC interacts with the
TCR.

1. Signal is transmitted by CD3 complex thru several pathways that lead to a large influx of Ca+
into the cell
2. Ca+ activates calcineurin, a serine phosphatase
3. Calcineurin activates genes for IL-2 and the IL-2 receptor
4. IL-2 (T cell growth factor) stimulates:
· Th to multiply into a clone of antigen-specific Th cells
à Most cells of this clone perform effector and regulatory functions, some become “memory”
cells
· Tc cells to produce gamma interferon
à IFN gamma _ expression of class II MHC proteins on APCs à enhances ability of APCs to
present antigen to T cells & upregulates immune response

Memory T cells

· Endow host defenses w/ability to respond rapidly and vigorously for many years after initial
exposure antigen
· This memory response to a specific antigen is due to:
o Many memory cells are produced, so that sec-ondary exposure is greater than primary response
o Memory cells live for many years or have the capacity to reproduce themselves
o Memory cells are activated by smaller amounts of antigen and require less costimulation
o Activated memory cells produce greater amounts of interluekins than do naïve T cells when
they are first activated

T cell receptor (TCR)

1. Similar to Ig heavy chains in that:

· Genes coding for them are rearrangements of DNAs
· There are V (variable), D (diversity), J (joining), and C (constant) segments that rearrange to
provide diversity
· Genes (RAG-1 and RAG-2) that encode enzymes that catalyze these rearrangements are similar
in T & B cells
2. Each T cell has a unique TCR on its surface
· Millions of different T cells exist in each person, and activated T cells (like activated B cells)
clonally expand
3. TCR is different in 2 ways:
· It has 2 chains rather than 4
· Recognizes Ag only in conjunction w/MHC proteins

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Effector functions of T cells

1. Delayed hypersensitivity
· Produced against antigens of intracellular microorganism
· Mediated by macrophages and CD4 cells (esp Th-1)
2. Cytotoxicity
· Concerned w/destroying virus-infected & tumor cells
· To kill virus-infected cell, Tc cell must recognize both viral antigens and class I molecules on
surface of infected cell AND receive a cytokine stimulus from a Th cell
· Note: Infected cell can also be killed by antibody-dependent cellular cytotoxicity (ADCC)

How do Tc and NK cells kill virus-infected cells?

1. By inserting perforins into infected cell

· Form channel thru pm à cell contents lost à cell dies
2. By inserting granzymes into infected cell
· Trigger apoptosis by activating caspases (which destroy DNA repair)
3. By activation of the Fas-Fas ligand (FasL)
· Fas is a protein on surface of many cells
· When a cytotoxic TCR recognizes an epitope on the surface of a target cell, FasL is induced in
the T cell
· When Fas & FasL interact, apoptosis of target cell occurs

Antibody-dependent cellular cytotoxicity (ADCC)

1. Combination of IgG and phagocytic cells that can destroy virus-infected cells
2. Ab bound to the surface of the infected cell is recognized by IgG receptors on the surface of
phagocytic cells (eg, macrophages or NK cells)
3. Infected cell is killed
4. This process can also kill helminths (worms)
· In this case, IgE is the Ab involved and eosinophils are the effector cells

Regulatory functions of T cells

1. Antibody production
· Most Ab production requires Th cells (T cell-depen)
2. Cell-mediated immunity
· Ag is processed by macrophages, is fragmented, and is presented w/class II MHC molecules on
the surface
· These interact w/receptor on Th cell à stimulated to produce lymphokines (IL-2 = T cell growth
factor) à stimulates specific Th and Tc cells to grow
3. Suppression of certain immune responses
· Certain T cells can suppress Ab production
· Failure of such regulation may result in unrestrained Ab production to self antigens
(autoimmune disease)

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T cell-dependent response

1. Ab production that requires the participation of Th cells

2. Ex. B cells used as APC (macrophages commonly do this):
· Ag binds to IgM or IgD & is internalized w/in B cell
· Ag fragments return to surface w/class II MHC mol.
· These interact w/TCR and, if B7 on B cell interacts w/CD28 on Th cell, Th cell produces IL-2,
IL-4, & IL-5
· IL-4 & -5 induce class switching (IgMàIgG, IgA, IgE)
· B cell divides and differentiate into plasma cells
· Interleukins alone are not sufficient to activate B cells:
à CD40 ligand must interact w/CD40 on B cell
à Other proteins strength interaction between Th and B cell (LFA-1 on T cell w/ICAM-1 on B
cell)

T cell-independent response

1. Antibody production that is not dependent on Th cells

2. Antigens that induce such a response are usually polymerized (multivalent) macromolecules
such as bacterial capsular polysaccharide, DNA, RNA, many lipids
· Repeated subunits act as a multivalent antigen that cross-links the IgM antigen receptors on the
B cell and activates it in absence of help from CD4 cells
3. Primarily IgM is made (vs. T cell-ind response where all classes of Ab are made)
· This indicates that the lymphokines produced by the Th cell are needed for class switching
4. Does NOT generate memory B cells

B cell functions

1. They differentiate into plasma cells and produce antibodies

2. They are APCs

B cell origin

1. B cell precursosrs first in fetal liver, then migrate to bone marrow where they remain during
adult life
2. Maturation of B cells has 2 phases:
· Antigen-independent phase
à Consists of stem cells, pre-B cells, and B cells
· Antigen-dependent phase
à Cells that arise subsequent to interaction with antigen (eg, activated B cells and plasma cells)
3. B cells display surface IgM, the antigen receptor
· Surface IgM = monomer (circulating IgM = pentamer)
4. Located in germinal centers of lymph n, white pulp of spleen, GALT

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B cell surface markers

1. Surface immunoglobulin (slg)

· Receptor for antigen (the B cell receptor)
· B cell-receptor complex = slg+Iga+Igb
à Iga and Igb - heterodimer accessory molecules that appear on either side of slg; similar to CD3
complex of T cell à both function as signaling molecules when antigen binds to B cell-receptor
complex
2. Complement receptors (CR1 and CR2)
3. Fc receptors
· Binds to Fc portion of Abs

Activation of B cell

Recognition phase:
1. Antigen binds to B cell IgM or IgD, endocytosis of antigen
Activation phase:
1. Antigen epitopes appear on surface w/class II MHC proteins
2. Complex is recognized by Th cell w/a receptor for antigen
3. T cell produces IL-2, IL-4, IL-5 à growth & differentiation of B cell, isotype switching to IgG,
affinity maturation
4. Costimulatory interactions must occur for full activation:
· CD28 on T cell must interact w/B7 on B cell
à Required for activation of T cell to produce IL-2
· CD40L on T cell must interact w/CD40 on B cell
à Required for class switching to IgG & other classes

End result of B cell activation

Effector phase:

1. Mature IgM and IgG expressing B cells produced

· IgM is most effective in activating complement
2. Plasma cells produce Igs specific for the epitope
· Secrete thousands of Ab/sec for few days then die
3. Some activated B cells form memory cells
· Can remain quiescent for long periods but are capable of being activated rapidly upon re-
exposure to antigen
· Most have surface IgG as Ag receptor, some have IgM
· Memory T cells secrete ILs that enhance memory B cell antibody production
à Thus rapid appearance of Ab in 2ndary response

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Macrophages (mononuclear phagocytes/monocytes)

1. Kidney shaped nucleus, large (10-20mm), granules w/lots of enzymes (ex. peroxidase, lipase,
protease, elastase, etc.)
2. Three main functions (1st – CMI, 2nd – humoral function):
· Phagocytosis – surface Fc receptors interact w/Fc portion of Igs, enhancing uptake of opsonized
organism
· Antigen presentation – present antigen fragments in association w/class II MHC for interaction
w/the TCR
· Cytokine production – IL-1 and TNF
à IL-1 – activates Th cells
à TNF – imp inflammatory mediator
3. Derived from bone marrow histiocytes
4. Markers: MHC class II, Fc receptors, complement receptors

Granulocytes

All have polymorphonucleus, intermediate size, brightly stained granules

1. Neutrophils (70% of blood)
a. Predominant in blood, acute phase, phagocytic, release enzymes
b. Markers: Fc and complement receptors
2. Eosinophils (5% of blood)
3. Basophils (1% of blood

Natural killer cells (NK)

1. Imp role in innate host defenses

2. specialize in killing virus-infected cells and tumor cells
3. Can kill w/o Ab, but Ab enhances their effectiveness (ADCC)
4. Potently activated by IL-12 and gamma IFN
5. Have receptors that detect presence of class I MHC
· If cell displays sufficient class I MHC – cell is not killed (and vice versa)
6. Kill by producing perforins and granyzmes, which cause apoptosis of target cell

Eosinophils

1. Its count is elevated in:

· Parasitic diseases (especially nematodes)
· Hypersensitivity diseases (eg, asthma, serum sickness)
2. Stimulated by IL-5
3. Function not clearly established
4. Likely their main function is to defend against migratory larvae and discharge contents of their
granules, which damages the cuticle of the larvae
5. May also mitigate effects of immediate hypersensitivity rxns b/c granules of eosinophils
contain histaminase (enzyme that degrades histamine), which is an important mediator of
immediate rxns

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Basophils and mast cells

1. Basophils
· WBCs w/blue granules
· Circulate in blood stream
2. Mast cells
· Fixed in tissue (esp under skin and in mucosa of respiratory and GI tracts)
3. Both:
· Have receptors for Fc portion of heavy chain of IgE
· When adjacent IgE molecules are cross-linked by antigen, histamine and enzymes (eg,
peroxidases, hydrolases) are released à inflammation and, in large amounts, cause severe
immediate hypersensitivity rxns

1. IL-1

2. IL-2

1. Produced mainly by macrophages, also epithelial cells, etc.

· Stimulator of inflammation (innate) & T cell (specific immunity)
· Its release is stimulated by LPS and T cells
· _ cAMP, _ nuclear factors, _ prostaglandins, _ adhesion molecules
· High concentrations _
- Endogenous pyrogen (Fever)
- Cachexia
· Activates T & B cells, neutrophils, epithelial, fibroblasts
· Ex. stimulates Th cells to differentiate and produce IL-2
2. Produced mainly by Th-1 cells
· Activates helper and cytotoxic T cells
· Activates B cells (acts synergistically w/IL-4)
· Induces LAK (lymphocyte activated killer) cells

1. IL-4

2. IL-5

1. Produced mainly by Th-2 cells

· Promote growth of B cells
· Enhances humoral immunity by _ Th-2 cells
· Required for class switching, enhances IgE synthesis
2. Produced mainly by Th-2 cells
· Promote differentiation of B cells
· Enhances synthesis of IgA
· Stimulates production and activation of eosinophils

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1. IL-6

2. IL-3

1. Produced by Th cells
· Stimulates B cells to differentiate
· Induces fever
· Induces production of acute-phase proteins in liver

2. Made by Th-2 cells

· Mediator of allergic airway disease (asthma)
· Shown to cause asthma in animals
· Involved in producing airway hyperresponsiveness

IL-10 and IL-12

1. Regulate the production of Th-1 cells

· IL-12: produced by macrophages, promotes Th-1 cells
· IL-10: produced by Th-2 cells, inhibits Th-1 cells (by limiting gamma IFN production)
2. Relative amts of IL-4, IL-10 and IL-12 drive differentiation of Th-1 and Th-2 cells
· Therefore enhance either CMI or humoral immunity
· Imp medical consequences b/c main host defense against certain infections is either CMI or
humoral
à Ex. Leishmania infections in mice – lethal if humoral response predominates but controlled if
CMI predominates

1. IL-13

2. Transforming growth factor-b (TGF-b)

1. Mediator of allergic airway disease (asthma)

· Made by Th-2 cells
· Binds to a receptor that shares a chain w/IL-4 receptor
· Involved in producing the airway hyperresponsiveness seen in asthma but does NOT _ IgE
2. Inhibits growth and activation of T cells
· “Anti-cytokine”
· Also inhibits macrophages, B cells, neutrophils, NK cells
· Stimulates wound healing by _ synthesis of collagen
· Dampens/suppresses immune response when its no longer needed, promotes healing process

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Interferons

1. Block virus replication

· Alpha IFN
à Produced by leukocytes
· Beta interferon
à Produced by fibroblasts
2. Act as Lymphokines
· Gamma IFN
à Produced primarily by Th-1 and Tc cells, NK cells
à Potent activator of phagocytic activity of macrophages, NK cells, and neutrophils
à Can also _ synthesis of class I and II MHC proteins (thus enhancing antigen presentation)

Tumor necrosis factor (TNF-a)

1. Inflammatory mediator released primarily by macrophages

2. At low concentrations à beneficial effect
· _ synthesis of adhesion molecules by endothelial cells
· Activates respiratory burst w/in neutrophils
· _ lymphokine synthesis by Th cells
· Stimulates growth of B cells
3. At high concentrations à
· Mediator of endotoxin-induced septic shock
· Cachectin b/c it inhibits lipoprotein lipase in adipose, thereby _ utilization of fatty acids (results
in cachexia)
· Causes death and necrosis of certain tumors in animals
· Endogenous pyrogen

1. Lymphotoxin/TNF-b

2. Nitric oxide (NO)

3. Macrophage migration inhibitory factor (MIF)

1. Made by activated T cells, same effects as TNF-a

2. Functions:
· Mediator made by macrophages in response to endotoxin
· Vasodilation (mediator of hypotension in septic shock)
3. Functions:
· Mediator made by macrophages in response to endotoxin
· Major role in induction of septic shock

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CD Leukocyte Markers

1. CD2 - costimulatory molecule that binds to LFA3 (integrin)

· On T and B cells, NKs, macrophages, neutrophils
2. CD3 – TCR coreceptor
3. CD11a – a costimulatory molecule that binds to ICAMs
· On T and B cells, NKs, macrophages, neutrophils
4. CD16 – another name for Fc receptor
5. CD19 – B cell coreceptor
6. MHC II – on APCs (T cells, B cells, macrophages)
· Bind to Ag, CD4
7. MHC I – on T and B cells, NKs, macrophages, neutrophils
· Binds to Ag, CD8

1. Primary lymphoid organs

2. Secondary lymphoid organs

1. Foster the maturation of naïve stem cells

· Thymus, bone marrow, bursa of Fabricus (in chicken)
2. Contain mature cells and foster immune response
· Lymph nodes, spleen, and GALT
· Foreign Ag driven (unlike primary lymphoid organs)

Are both composed of lymphocytes, accessory cells (eg, APCs) and epithelial cells
· Epithelial cells can secrete factors that help in maturation and development of immune response
o Ex. thymic epithelial cells secrete thymosin, which promotes T cell maturation

Thymus

1. Fosters maturation of T cells

2. Lymphoepithelial
3. Divided into cortex and medulla
4. Contain macrophages and dendritic cells that present self-antigens to differentiating T cells
leading to positive and negative selection
5. Stem cells originally from bone marrow enter cortex à positive and negative selection ensues
at corticomedullary junction
6. Positively selected cells go on into medulla and out into body to secondary organs

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Bone marrow

1. Contains all the cells and cytokines necessary for B cell development
2. preB à immature B à mature B

Spleen

1. Filters antigen out of blood and promotes immune response

2. No spleen à more susceptible to blood-borne infections
3. Composed of capsule and reticular and cellular framework
4. Contains lymphocytes, APCs, and RBCs
5. Divided into red pulp surrounding the white pulp
· White pulp surrounds central artery
à Contains PALS (peri-arteriole lymphatic sheath) which is where most of the T cells are located
à B cells clustered in germinal centers
6. Blood flow enters via central branches of trabecular a. à white pulp/PALS à lymphatic nodule
à marginal zone à red pulp à pulp veins à trabecular veins à splenic vein

Lymph nodes

1. Filters Ag from the lymph and supports immune response

2. Composed of capsule, cortex and medulla
· Outer cortex à follicle or B cell zones
· Inner cortex à T cell zones
· Medulla à Location of plasma cells
3. Same structure as spleen: B cells surrounded by T cell
4. Artery associates w/ high endothelial venule/HEV à this is how components return to lymph
from the blood
5. HEVs are specialized and found only in this area – allow WBCs to get out of blood and into
lymph node
· Imp if you have an infection in a node, lymphocytes of right clone can be “called out” of blood
into node

Factors affecting immunogenicity

1. Protein complexes and particulate antigens are better than non-complexed proteins or soluble
antigens (i.e. they engage APCs better à better immune response)
2. Route
· Subcutaneous injection give best immune response
· Intradermal (I.D.) also good
3. Dose
· Too little or too much can be inhibitory
4. Adjuvants
· Substances that mix w/antigen thus engaging APCs
· Vaccines are given w/adjuvant (eg, Freund’s adjuvants)
5. Immune response potential (immune responses are variable)

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Rank order for antigen potency

1. Proteins > polysaccharides > nucleic acids > lipids

2. Proteins are best immunogens
· Easily processed by APCs
· Easily form non-covalent bonds w/MHC molecules and T and B cell receptors
· Complex proteins contain multiple epitopes per protein molecule à arouses many clones (eg
more than 1 T cell and/or B cell can bind to its various epitopes, thus eliciting different clones)

Lipopolysaccharides

1. Are endotoxins
2. T-independent antigens (induce T-indep immune responses)
· Very limited immune response
3. Contain 3 functional groups:
· Lipid A group – stimulates B cells
à Combines w/a serum protein
à This complex then binds to CD14 on B cells
· Core polysaccharide
· O antigen polysaccharide – binds to B cell receptors (if that receptor is a clone w/affinity to O
antigen)

ABO Red Blood Cell antigens

1. Type O has Ab to both A and B, Type A has Ab to B, etc.

2. “Type and cross”
· Type = tests RBCs w/antibodies to detect antigens
· Cross-matching = tests serum for Abs
3. Rhd – glycoprotein on RBC surface
· Rhd+ = gene is expressed, Rhd- = gene is silent
· Ex. wife is Rh- and husband is Rh+
à Fetus likely to be Rh+ à mother begins to make Abs to Rh. If Ab is IgG it can cross placenta
and result in hemolytic disease of newborns
à Will manifest only at a 2nd or later pregnancy
à Treatment:Rogam (anti-Rh Ab given during labor)

1. Isotypes

2. Allotypes

3. Idiotypes

1. Are defined by antigenic (amino acid) differences in their constant regions

· Ig classes are different isotypes – their H chains are antigenically different (all variants present
in serum)
2. Antigenic features of Igs that vary among individuals

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· B/c individuals have different alleles for L and H chains
3. Antigenic determinants formed by specific amino acids in hypervariable region, thus specific
to each Ig molecule
· Each is unique for the Ig produced by a specific clone of Ab producing cells
· Anti-idiotype Ab reacts only w/hypervariable region of Ig that induced it

Immunoglobulin classes

1. IgG (75%) – monomer, H chain symbol = gamma

2. IgA (15%) – monomer or dimer, H chain symbol = alpha

Secretory IgA prevents attachment of microbes to mucous membran
3. IgM (9%) – monomer or pentamer, H chain symbol = mu

4. IgD – uncertain function. On B cell surface. H chain = delta

5. IgE – monomer, H chain symbol = eta

1. L chains (light chains)

2. H chains (heavy chains)

1. Belong to one of two types, k (kappa) or l (lambda)

· Both types occur in all classes of Igs, but only one Ig molecule contains only one type of L
chain
· Amino-terminal portion of each L chain participates in antigen-binding sites
2. Distinct for each of the five Ig classes
· Designated g, a, m, e, and d
· Amino terminal portion of each H chain participates in antigen-binding site
· Carboxy terminal forms the Fc fragment

How many domains do the H chains have in each of the 5 classes of immunoglobulin?

What do unique sequences in the H chains allow for?

1. IgG, IgA, and IgD H chains have 3 constant domains

2. IgM and IgE H chains have 4 constant domains
3. All L chains (both kappa and lambda) have 1 constant domain

Unique sequences in the H domains allow for isotypic variation (common to all members of the
species), allotypic variation (variation between members of the species), complement binding, Fc
binding, and disulfide bond formation.

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Domain positions in IgG

1. Domains are loops of peptide stabilized by intra-chain disulfide bridges

2. Each light chain has 1 variable and 1 constant domain
· VL and CL
3. Each heavy chain has 1 variable and 3 constant domains
· VH, CH1, CH2, and CH3
4. Remember: each heavy chain is identical to the other heavy chain in the immunoglobulin
molecule, same w/light chain
5. Antigen binds to “variable regions”
6. Each IgG molecule is bivalent, i.e., it has two identical binding sites for antigens

Fab and Fc positions

1. Fab
· Portion of IgG that binds the antigen
· Composed of entire light chain and the variable and 1st constant domain of heavy chain (VL,
CL, VH, and CH1)
2. Fc
· Terminal end of heavy chain (carboxy end)
· Controls the biological activity
· Contain amino acid regions that confer function such as complement activation and binding to
Fc receptors
· Ex. amino acid sequence Glu-Lys-Lys in Cg2 domain of IgG is needed for C1q of complement
to bind to IgG

Hypervariable regions

1. Amino acid sequences in the variable domains of H and L that are unique from one Ig to the
next
2. Called “complementarity determining regions” (CDRs)
3. There are 3 CDRs in each H and L chain
4. Where the antibody makes actual contact with the antigen
5. Amino acid residues of antigen epitope form noncovalent bonds w/amino acids lining the
binding site on the Ab
· These weak noncovalent forces become stronger as the fit between Ag epitope and combining
site _
6. These variations are called idiotypic variations b/c they vary w/in a single member of a species
7. Every human serum contains Igs of many different idiotypes

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CDRs and affinity and specificity

· The better the antigenic epitope fits into Ab binding cleft (i.e. high specificity), the # and
strengths of the bonds _
· _ association = _ affinity constant (K) = _ binding strength
· Specificity is relative in that binding clefts can accommodate cross-reacting antigenic epitopes
· Inject multivalent antigen into an animal à antiserum containing Abs of multiple specificities &
affinities
· Affinity and specificity mature w/time after immunization

1. Allotypic markers

2. Immune clearance

1. Additional antigenic features of Igs that vary among individuals (their biological function is
unknown)
· Are found in the:
à Fc portion of the H chain
à Constant portion of the L chain

2. Phenomenon where, generally, Ab-Ag binding facilitates the binding of Ab to Fc receptors on

phagocytic cells

IgM Structure

1. Pentameric – “J chain” links five subunits/chains of Ig together resulting in a pentamer

2. Has 20 chains and conceivably can bind to 10 antigens
3. Only one is needed to activate complement system b/c it comes pre-packaged w/2 Fc receptors
close to each other

Secretory IgA structure

1. Dimer – J chain connects 2 Igs together

2. Also has a secretory piece that’s added to help protect from proteolytic digestion which it gets
into secretions
3. Note: secretory piece is NOT present on serum IgA

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IgG

1. Consists of 2 L chains and 2 H chains linked by disulfide bonds (divalent)

2. Four subclasses
3. Directed against polysaccharide antigens
4. Important defense against encapsulated bacteria
5. Predominant Ab in secondary response
6. Only antibody to cross placenta – most abundant Igs in newborns
7. Opsonizes (ie, enhance phagocytosis)
8. Neutralizes virus or toxin upon binding to it

IgA

1. Main immunoglobulin in secretions (colostrum, saliva, tears, respiratory, intestinal and genital
tract secretions)
2. Prevents attachment of bacteria and viruses to mucous membranes
3. Each molecule consists of two H2L2 units + J chain and secretory component
· Secretory component – polypeptide made by epithelium
à Provides for IgA passage to mucosal surface
à Also protects IgA from being degraded in intestinal tract
4. Neutralizes toxin or virus upon binding to them

IgM

1. Two forms created via alternative mRNA splicing:

· Secreted: main Ig produced early in primary response
· Membrane – bound: on surface of B cells where it functions as an antigen-binding receptor
(BCR)
à Accessory proteins a/b à activate src-family tyrosine kinases
à Signals differentiation to plasma & memory cells
2. BCR is a monomer
3. In serum, it is a pentamer (5 H2L2 units + J chain)
4. Has 10 Ag-binding sites (highest avidity) à most efficient Ig in agglutination, compement
fixation, & other rxn
5. Imp in defense against bacteria and viruses

IgD

1. Has no known Ab function

2. May function as an antigen receptor since it is present on surface of many B cells
3. Present in small amounts in serum

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IgE

1. Mediates immediate (anaphylactic) hypersensitivity

2. Participates in host defenses against certain parasites (eg, helminths)
3. Its Fc region binds to surface of mast cells and basophils
4. Bound IgE serves as a receptor for antigen (allergy)
· This An-Ab complex triggers allergic responses of the immediate (anaphylactic) type thru
release of mediators
5. Present in trace amounts in normal serum
6. Persons w/allergic reactivity have __ amounts
7. May appear in external secretions

Fc Receptors

1. Fcg receptors à on phagocytes

· Bind immune complexes – promote phagocytosis
· On Tc and NK cells – regulate ADCC
· On trophoblast and endothelial cells of placenta – transport IgG into fetal circulation
2. Fce receptors à on mast cells
· Bind IgE – triggers degranulation and allergy
3. Fca receptors à on basal surface of intestine epithelium
· Bind dimeric IgA – promote transport of complex thru cell to gut lumen
· Portion is cleaved & remains w/IgA as secretory piece

1. How many gene segments code for V region of L chains?

2. How many gene segments code for V region of H chains?
3. What does antibody diversity depend upon?
4. In the synthesis of the H chain, what two segments are expressed first (and are present in the
primary RNA transcript)?

1. 2 gene segments (V + J)
· V codes for first 95 residues
· J codes for 13 residues
2. 3 gene segments (V + D + J)
3. a) Multiple gene segments for Variable regions
b) their rearrangement into different sequences
c) combining different L and H chains in assembly of Igs
d) mutations (responsible for affinity maturation)
4. Mu (m) and delta (d) (IgM and IgD H chains)
· Delta lacks a switch region, thus “comes along for the ride” with mu
· Two H chains produced will either have mu or delta

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Class Switching

1. Initially all B cells carry IgM specific for an antigen

2. Later, gene rearrangement permits elaboration of Abs of same antigenic specificity but of
different Ig classes
3. Occurs ONLY with HEAVY CHAINS
4. Same VH (variable H) gene can associate with different CH (constant H) genes so that Igs
produced later (IgG, IgA or IgE) are specific for same antigen as original IgM
5. A different mechanism is used in switch from IgM to IgD
· A single mRNA is transcribed --> IgM & IgD mRNAs
· Thus mature B cells can express both IgM and IgD
6. Note: once B cell has switched pass a certain H-chain gene, it can no longer make it b/c
intervening DNA is discarded

1. How are cytokines involved in class switching?

2. Generation of TCR diversity

1. IL-4 increases IgE, IL-5 (from T cells) increases IgA

2. Ag binding portion of TCR is generated by 4 sets of genes: alpha and beta (on majority of T
cells), & gamma and delta (expressed on subpop of T cells)
· General arrangement of TCR genes similar to H chains
· Diversity is generated by:
à Multiple germ-line genes
à VJ and VJD recombination
à Joining site variation
à Multiple D region
à N-region diversification (random base inserts)
à NO somatic mutations for T cell diversity

Hyper IgM immunodeficiency

1. X-linked trait, CD40 gene mutation

2. Interaction of the CD40 protein on B cell with CD40 ligand protein on the Th cell is a
controller of class switching
3. Failure of this interaction to occur results in an inability of the B cell to switch to production
of either IgG, IgA or IgE
4. Therefore, only IgM is made
5. Patient presents with:
· _ IgM, _ IgG
· Normal numbers of T cells and B cells
· Recurrent pyogenic infections (b/c these require IgG)
6. Treat with passive immunotherapy – IV gamma globulin from a pool of donors

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Functions of the complement system

- cytolysis – complement binds to Ag-Ab complex and directs lysis of certain cell types; only
certain bacteria are susceptible to lysis, also happens to some body cells (RBCs)
- opsonization – certain phagocytic cells that have complement receptors will recognize the
complement-Ab complex and opsonize the antigen
- inflammation – in the cascade, there are products of the complement system being produced
called anaphylatoxins. These products have two roles:
- recruit inflammatory cells to the area
- activate these cells to produce mediators that will lead to additional inflammation. This will
help in Ag clearance

Two Limbs of the Complement System – Classical and Alternate

- similarities
- both consist of inactive proteins -- zymogens
- both are highly regulated – there are regulatory proteins at every step in the process
- both involve enzymatic cascades
- both end with the membrane attack complex (MAC)
- difference is in how they are initiated
- the classical system starts with antigen-antibody complex
- the alternative system doesn’t need antibody to start
- alternative system used by Gram- and Gram+ bacteria, fungal & yeast cell walls, tumors,
parasites, etc.

1. Which antibodies are involved in the complement system?

2. How does C1 travel in the body and how/where/when does it bind to Ab-Ag complex?
3. What produces complement components?

1. IgM and IgG ONLY

· C1 must bind to 2 Fc regions for cascade to occur
· IgM much more efficient for b/c only need 1 IgM as opposed to 2 IgGs (to actually have 2 IgGs
close enough for C1 to bind both requires at least 1000 IgG molecules)
2. C1 travels in circulation bound to an inhibitor
· when it sees Ag-Ab, inhibitor is cleaved off and C1q component of C1 is able to bind to Fc
portion of Ab
· Then the cascading starts
3. Hepatocytes and mononuclear phagocytes

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Alternate pathway

1. Spontaneous activation (autolysis) of C3 into C3a and C3b – this process is called “tickover”
2. C3b then binds to the cell membrane by itself
· When C3b binds to self cells _ inactivated
· When C3b binds to foreign cells _ it sticks
3. Binding of C3b leads to activation of other components
4. Factor B interacts w/C3b _ proteolyzed by factor D to form C3bBb (C3 convertase) (different
from classical path)
5. C3 convertase then activates another C3 to form C3b
6. C3b combines with C3 convertase to form C3bBb3b (C5 convertase) (also different from one
in classical path)
7. C5 convertase then interacts w/C6, 7, 8 and 9 to form MAC

Control of the Classical Pathway

1. Time – complement components need to be under fine control, don’t want too much firing
leading to constant inflammation (unbound components active for nanosec)
2. Receptors – different CRs on different cells
· CR1 – B cells, PMNs, monocytes, macrophages
· CR2 – B cells, dendritic cells
· CR3 – monocytes, macrophages, PMNs, NK cells
· CR4 – PMNs, monocytes, macrophages
3. Specific factors – regulatory factors that have very specific actions in limiting the complement
system
· Ex: CCP and DAF inhibit C3 convertase
· MCP degrades C4b

What would a deficiency of the following result in:

1. Early complement components (Clq, r, s OR C4 OR C2)
2. Late components
3. Regulatory factors
4. Complement receptors

1. Still can kill microbes via alternative pathway but…

· Chronic pyogenic infect. (they need to be phagocytized)
· Immune complex disease: Failure to clear Ag-Ab complexes _ vasculitis, glomerulonephritis
2. Chronic Neisseria infections
3. C1H (C1 inhibitor) deficiency _ autosomal HANE
· “Hereditary angioneurotic edema”
· Overactive system leading to chronic inflammation.
· C1 is not inhibited _ decreased levels of C4
4. Leukocyte adhesion deficiency (LAD)
· Inflammatory cells can’t come since they are missing a CR leading to pyogenic infections

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Examples of lab tests that are based on:
1. Primary unions/interactions
2. Secondary unions/interactions
3. Tertiary unions/interactions

1. Immunoflourescence, ELISA, flow cytometry

2. Precipitation (pptn), agglutination, RID
3. Complement fixation test

1. Class I MHC proteins

2. Class II MHC proteins

1. Composed of a chain and b2-microglobulin non-covalently bound together

· Antigen binds to a portion
· 8 amino acids
· b2-microglobulin gene is on chromosome 15
· Present viral antigens
2. Class II – composed of a and b chain
· Antigen binds to alpha 1 group and beta 1 group
· 30 amino acids
· Both chains encoded for on same chromosome
· Present extrinsic antigens such as bacteria

1. What does innate CMI refer to?

2. What does adaptive CMI refer to?

1. Depends on cellular and humoral elements of inflammation; does not involve T cells directly
· Sets up stage for adaptive immunity
· Includes chemotaxis, phagocytosis, acute phase proteins, and inflammatory mediators
(histamine, serotonin, PAF, IL-8, C3a, C5a, bradykinin, PGs, leukotrienes, etc.)
2. Depends on T helper and cytotoxic cell functions
· Note: cytotoxic effectors include CD8 T cells, NK cells and macrophages
· CD4 cells stimulated by antigen from APCs _ grow and proliferate _ cytokine secreting and
memory cells

Hashimoto’s thyroiditis

1. Diffuse infiltration of thyroid w/lymphocytes, resulting in diffuse goiter, destruction of

parenchyma and hypothyroidism
2. Presents w/painless swelling in neck forming over 2-3 years
· Pertinent findings: enlarged thyroid, T3, T4, and TSH normal; serum contains anti-
thyroglobulin and anti-thyroid microsomal (Abs to thyroid tissue)
3. Patient returned complaining of lethargy, slowness of movement, memory loss, and weight
gain

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· Pertinent findings: _ T3 and T4, _ TSH, anti-thyroid antibodies _ from first visit
4. Etiology of disease is the production of Abs to thyroid Ags

Immune Regulation

1. Antibody dependent B cell suppresion

· Blocking antibody: high doses of Ig block binding of antigenic determinant (epitope) and
membrane Ig on B cells (ex. Rogam)
· Receptor cross linking: Low doses of Ab _ antigen cross-links B cell’s Fc receptors and its
antigen receptors
à Tyrosine phosphatase activate _ inhibits cell activation
2. Regulation by immune complexes – either augment or inhibit response
· Inhibition: Fc receptor of B cell cross links w/Ag receptor by Ag-Ab complex _ signals B cell
to stop antibody production phase
· Augmentation: APC-bound Ab _ presentation of Ag to B cells
3. Anti-idiotypes – can either suppress or enhance immune response
· Produced to either non-antigen binding sites (paratopes) or to antigen binding sites (idiotopes)
4. Immune repertoire – MHC and non-MHC genes polymorphisms

Tumor specific antigens (TSAs)

1. Unique to cancer cells

2. Not found on normal counterparts
3. Arise through point mutations
4. Unique to a single neoplasm arise through point mutations in DNA damaged by carcinogenic
chemicals, UV or X radiation, viral infections:
· hep B
· human T cell leukemia virus
· HPV _ cervical cancer
· Epstein Barr _ Burketts lymphoma

Tumor associated antigens (TAAs)

1. More often found on tumors rather than TSAs

2. Found on both normal and malignant cells, but their expression is increased on tumor cells
3. Examples
· CEA (carcinoembryonic antigen) _ predictor of recurrence of colon cancer (200 ng/ml) (levels
_ when cancer is present and drops when it is removed)
à Also used as prognosticator for metastasis
à Normal level: ~10ng/ml
· AFP (alpha feto protein) _ elevated in liver and testicular cancer (not absolute, can be raised in
cirrhosis and COPD) (very suspicious if >500ng/ml)

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Immune response to tumors

1. Humoral
· IgG & IgM Abs that fix complement destroy soft tumors
· Abs against tumors impede adhesion some tumors need
· IgG Ab may mediate destruction of tumors via ADCC
2. CMI _ MOST IMPORTANT mechanism (esp Tc cells)
· Macrophages activated by T cell derived IFN gamma kill tumor cells (TNFa, lysozyme, O2
radicals)
· NK cells kill tumors by same mechanism they use to kill virus infected cells (cell w/_MHC _
signals NK)
· Tc kill tumors in Ag specific & MHC restricted way
· CMI is so imp b/c antigens made by tumors are processed by the endogenous pathway

Presentation of tumor antigen to immune system

Can occur in one of three ways:

1. MHC I+ but B7— expressing tumor cell encounters Tc cell
· Results in anergy b/c need B7 to activate Tc cells
· Mechanism by which tumors evade immune response
2. MHC I+ and B7+ expressing tumor cell encounters Tc cell
· Results in Tc activation
3. APC present processed tumor Ag to Th cells
· Tumor cell sheds antigen _ APC phagocytizes & presents Ag to Th cell _ Th cell activates &
secretes cytokines _ Tc cell activated _ Tc destroys tumor cell
· NOTE: Tumor cells DO NOT express MHC II, so they rely on APCs to get Th cell response

Mechanisms tumors use to evade the immune response

1. Lack of co-stimulatory molecule (B7) on tumor cells

· Most tumor cells are poor APCs since they lack B7
· May also lack adhesion molecules (LFA-3, ICAM-1)
· Some show a _ or complete loss of MHC I _ prevents tumor recognition by Tc cells (though it
attracts NK)
2. Block antibodies
· Ab + shed tumor Ag complexes can saturate Fc receptors on macrophages, neutrophils, NK and
Tc cells
· Prevents these effectors from interacting w/tumor cells
3. Secretion of suppressive factors
· TGF beta, prostaglandin E2 _ inhibit T cells
· Mucin _ anti-adhesive molecule

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Cancer immunotherapy

1. Anti-Cancer vaccines
· Immunization against oncogenic viruses
· More difficult to vaccinate against non-viral origins, ex:
à BCG (enhances responses against melanoma)
à Transfection of genes for B7, IL-2, IL-4, IFN gamma, GM-CSF (_ response of T cells)
à Naked DNA constructs (induces Tc cell)
2. In vitro activation of LAK cells & TIL (tumor infiltrating lymphocytes) with IL-2
3. Monoclonal antibodies (Mabs) made w/mice spleens
· Problem: HAMA response (human anti-mouse Ab response); Solution: chimeric Mabs

1. Heteroconjugate Mabs
2. Chimeric Mabs

1. Bi-specific Mabs that have 2 Fab regions:

à One against CD marker (ex. CD16 _ NK marker)
à One against tumor Ag
2. Mabs made up of:
à Human constant region
à Murine VL and VH regions
· Show a decreased HAMA response
· “Humanised” Ab _ advanced chimeric Ab
· Herceptin _ humanised Ab in metastatic breast CA
à Binds HER-2/neu, growth factor rec.on tumor cells
à Only Mab shown to be effective

Cytokine therapy for tumors

1. IFN alpha
· Remission in hairy cell leukemia pts
· Possible cytostatic effect on tumor
2. IFN gamma
· Ineffective systemically, remission of ovarian CA
· _ expression of MHC class I, cytostasis
3. IL-2
· Remissions in renal cancer and melanoma
· T cell activation and proliferation, NK cell activation
4. TNF alpha
· Can _ malignant ascites
· Macrophage & lymphocyte activation

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1. Innate immunity to bacteria
2. Adaptive immunity to bacteria

1. Various bacteria contain antigens in their cell envelopes and walls ranging from LPS to
lipoarabino-mannan
· Antigens interact w/serum factors & cells _ inflammat, influx of complement, phagocytes,
cytokines (IL-12)
· Bacteria killed primarily by degradation in phagocytes
· Accomplished by both O2-dep and O2-indep killing
2. Antibodies play imp role in resistance to bacteria
· Bind to bacteria _ prevent attachment to host, activate phagocytosis & complement, prevent
nutrient transport
· Also neutralize toxins released from bacteria
· CMI (T cells and macrophages) important in fighting intracellular bacteria

Describe the innate pathway triggered by bacteria.

1. Acute phase proteins bind to CHO moieties on bacterial surface _ alter complement pathway _
C3a, C5a _ vascular permeability, chemotaxis, etc.
2. Formyl peptide, muramyl peptide, peptidoglycan, Lipoproteins, lipoteichoic acid, LPS,
lipoarabinomannan
· Break down products of bacterial cell wall
· Activate NK cells, macrophages and PMNs, 2)interact w/blood clotting, platelet, plasmin
system
· In ALL bacteria
· Specific for gram-positive bacteria
· Specific for gram-negative bacteria
· Specific for acid-fast bacteria

Describe adaptive immunity mechanisms against bacteria.

1. Antibodies esp imp for extracellular bacteria:

· Fimbriae, lipoteichoic acids BLOCK attachment
· Transport mech., receptors BLOCK proliferation
à Also ENHANCE phagocytosis
· Envelope Ag., Fc and C3 receptors ENHANCE lysis
· Toxins BLOCK toxic effects
2. CMI to bacteria especially imp for intracellular bacteria:
· Ex of intracell bacteria: M. tuberculosis, Salmonella typhi, Legionelle pneumophils, Listeria
monocytoge, Chlamydia p., Brucella
· Immune system recognizes infected macrophage _ Th1 cells secrete IFNg and TNF _
macrophage activated _ kills bacterium

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Innate immunity to viruses

1. IFN _ produced by macrophages, T & other immune cells

· IFNg (immune) _ potent activator of APCs, Tc & NKs
à Also _ expression of MHC class II
· IFNa & b (non-immune) _ inhibit viral replication by inducing kinases that phosphorylate
translation factors (eIF-2) _ inhibits initiation of translation
· All _ expression of MHC 1 and B2 microglobulin
2. NK cells
· Important first line of defense, killing infected cells that are still low in MHC antigens
· Big producers of IFNs besides being activated by them

Adaptive immunity to viruses

1. Virus specific Abs can:

· Prevent infection by neutralizing virus (before attaches)
· Damage virus envelope by binding to virus and activating complement
· Promote viral-infected cell lysis (by complement, phagocytosis, and ADCC)
2. IgA in secretions _ protect mucosa-penetrating virus
3. CD8+ T cells _ main defense against virus infected cells
à Viral proteins associate w/MHC class I
à If __ _ virus becomes chronic and spreads
4. CD4+cells secrete cytokines(IFN,TNF)_activate phagocytes, provide setting for Tc cells to
kill target

Parasitic infection

1. 2 types: 1-celled protozoa, macroscopic metazoan/worms

2. Can exist either in cells or extracellularly
3. Generally: Ab best for extracell., CMI best for intracellular
4. Innate immunity to parasites:
· Phagocytic cells ingest small parasites
· Eosinophils _ resistance to worm infections
à Combine w/IgE & mast cells to provide resistance
à Activated by cytokines, kill by O2 dep & indep mechanisms
5. Adaptive immunity to parasites:
· CD8+ cells imp in killing cells parasitized by protozoa
· Th1 and Th2 also important:
à Th2 induces IgE, eosinophilia & mast cells
à Th1 enhances CMI

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Infectious mononucleosis

1. Presents w/malaise, sore throat, fever, headache, red throat, exudative tonsils, tender lymph
nodes
2. Monospot test positive
3. WBCs show lymphocytosis with atypical cells (T cells)
4. Virus infects epithelium of pharynx, producing sore throat
5. B cells then become infected: Epstein-Barr virus docks to CR2 on B cells, fibroblasts, and
epithelial cells
· Stimulates B cells to make polyclonal Abs (“heterophile Abs”), detected by the monospot test
6. So remember:
· The monospot response is the B cell response
· The atypical lymphocyte is the T cell

1. Passive immunity
2. Active immunity

1. Immediate immunity but transient

· Giving person preformed antibody
· Ex. hyperimmune Ig after infection or snake bite
· Ex. Passive transfer of Ig from mother to child
2. Delayed immunity but more permanent
· Ex. natural exposures to antigens in pathogens
· Ex. vaccines

Types of vaccines

1. Killed organism (ex Salk polio vaccine)

2. Ag part of disease causing organism (ex H. influenzae)
· Called “acellular”
3. Attenuated or “weakened” preparation (polio, measles)
4. Toxoid vaccines
· Toxins treated w/or absorbed w/aluminum salts
· Usually must add an adjuvant to _ immunogenicity
· Ex. diptheria & tetanus toxoids combined w/ pertussis (adjuvant)
5. Organism similar to virulent one (Jenner cowpox, BCG for TB)
6. Subunit vaccines (ex hep B)
· Genetically engineered
7. DNA plasmid vaccines
· Mimics live attenuated vaccine preps

Ways to give vaccines

1. Parenteral route (not po) _ mainly elicits IgG antibodies

· SubQ
· IM

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· ID (intradermal)
2. Oral route _ mainly elicits IgA antibodies due to GALT

1. Live attenuated vaccines

2. Killed vaccines
3. Vaccines based on subcellular microbial fragments

1. Polio, mumps, measles, rubella, yellow fever, varicella zoster, hepatitis A, TB

2.
· Very effective: Polio (salk) and rabies
· Moderately effective: Typhoid, cholera, influenza
· Debatable: Plague
· Controversial on basis of toxicity: Pertussis (cellular) –acellular pertussis vaccine that is less
toxic is now used
3. Haemophilus influenza, hepatitis B virus

Recommended childhood immunization schedule

1. Birth _ Hep B1
2. 1 – 4 months _ DTaP (diptheria, tetanus, acellular pertussis), Hep B2, and Polio
3. 6 – 18 months _ Hep B3, Hib (H. influenza type B), Polio, MMR (measles, mumps, rubella),
Var (V. zoster), HepA
4. 11-2 years _ tetanus (tetanus should be given every 10 yrs)

Adjuvants

1. Agents given with vaccines to enhance their immunogenicity

2. Mechanism:
· Depot effect (concentrate Ag in a particular area)
· Increase particle size of an antigen
· Increase release of cytokines
3. Examples:
· Inorganic salts (Aluminum OH, Aluminum PO4)
· Delivery systems (liposomes, BCG)
· Bacterial products (Freund’s adjuvant)
à Causes inflammatory granuloma response that increases immunogenicity

Non-specific immunotherapy

1. Microbial
· Filtered bacterial cultures: Coley’s preparation
· BCG: anti-tumor activity
2. Cytokines
· IFNgamma: leprosy, leishmaniasis
· IL-2: leishmaniasis
· GCSF: bone marrow restoration

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· BCG: anti-tumor activity
3. Cytokine inhibitors
· TNF antagonists: septic shock

Hypersensitivity reaction: Type I

(i.e. immediate or anaphylactic hypersensitivity)

1. Occurs when antigen binds to IgE on surface of mast cell

· IgE binds by its Fc portion to basophils and mast cells
· Reexposure to same antigen results in cross-linking of cell-bound IgE and release of active
mediators
2. Immediate response _ Wheel and Flare
· Wheel is result of histamine release
· Flare is result of
3. Late response (@ 5 hrs) _ lumps form (induration of cells)
4. Ex: Sea food, nuts, bees, wasps, hornets, ants, penicillin
5. Which clinical manifestation occurs depends on location of mast cells bearing IgE specific for
allergen
6. Most severe = systemic anaphylaxis (bronchocons., shock)

What are the active mediators released by mast cells in Type I hypersensitivity?

1. Histamine (preformed)
· Cause vasodilation, _ capillary permeability, smooth-muscle contraction
· Causes allergic rhinitis, urticaria, and angioedema
· Contributes to bronchospasms in acute anaphylaxis
2. SRS-A _ leukotrienes (NOT preformed)
· Cause _ vascular permeability, smooth-mus contraction
· Principle mediators in bronchoconstriction of asthma
3. Eosinophil chemotactic factor –A/ECF-A (preformed)
4. Prostaglandins and thromboxanes (NOT preformed)
· Cause dilation, _ vascular perm., bronchoconstriction
· Aggregate platelets

Type II hypersensitivity (cytotoxic)

1. Mediated by mainly IgG, but also IgM

2. Occurs when Ab directed at antigens of cell membrane activates complement _ MAC _ cell
lysis
· Macrophages also activated _ IL-1, TNF _ fever, etc.
3. Can occur with autoAbs or “altered self” (eg due to virus)
4. Examples:

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· Hemolytic disease of newborn (Rh reactions)
· Goodpastures syndrome: IgG Abs to glomerular BM
à Result: nephritis, proteinuria
à Lung also damaged b/c of similarities of BM
· Pemphigus: Abs to desmosome proteins
à Breakdown of cellular adhesions _ blistering

Type III Hypersensitivity

1. Mediated by immune complexes (IgG)

2. Antigen-antibody complexes are deposited in tissues
· Activates complement _ C3a, C5a
· PMNs to site_release lysosome enzyme_tissue damage
· Cytokines produced _ TNFa, IL-1
· Direct action on basophils and platelets
3. Arthus rxn (local inflammation)
4. Serum sickness (systemic inflammatory response)
· Results in fever, urticaria, arthralgia, lymphadenopathy, and eosinophilia days - 2 weeks after
injection
· Acute: 1large dose _ vasculitis, nephritis, arthritis
· Chronic: multiple injections _ kidney, arterial, and lung damage
à Ex. rheumatoid arthritis, Lupus

Type IV Hypersensitivity (delayed)

1. T cell mediated (only type NOT humorally related)

2. Can be caused by:
· CD8+ Tc cells attack skin cells (poison oak allergy)
· CD4+ Th cells sensitized _ lymphokines (TB skin test)
3. Contact hypersensitivity (12-72 hrs post-exposure)
· Occurs w/chemicals, plants, topical drugs, soaps, etc.
à Ex nickel, formaldehyde, poison ivy & oak, neomycin
· Act as haptens _ skin _ attach to body proteins _ complete Ag
· Result: erythema, itching, vesicles, or necrosis of skin
4. Tuberculin-Type (48-72 hrs post-exposure)
· Local induration (lymphocytes, macrophages)
5. Granuloma Type (21-28 days post-exposure)
· Ex. leprosy, TB, fungal infections

Patterns of infection

1. Humoral immunodeficiency – most common

· X-linked hypogammaglobulinemia (Bruton’s Agamma.)

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· IgA deficiency
· Common variable immunodeficiency
2. Combined B Cell & T Cell deficiencies
· Severe combined immunodeficiency disease (SCID)
· Ataxia telangiectasia
· Wiskott-Aldrich syndrome
3. T-cell immunodeficiency
· Thymic aplasia (DiGeorge’s syndrome)
· Chronic mucocutaneous candidiasis
4. Neutrophil/granulocyte immunodeficiency (rare)
· Leukocyte adhesion defect
· Chronic granulomatous disease
· Chediak-Higashi syndrome
· Job’s syndrome (Hyper IgE syndrome)
5. Complement deficiency (rare) – early and late deficiencies

What is the pattern of:

1. humoral immunodeficiencies?
2. Cellular (T lymphocyte) immunodeficiencies?
3. Neutrophil/phagocyte/granulocyte immunodeficiency?
4. Complement defects?

1. Recurrent sinopulmonary infections

· NOT a cold! sinusitis, pneumonia, otitis media, high grade pathogens
· _ occurrence of arthritis, autoimmune disease, viral gastroenteritis
2. Recurrent Opportunistic infections
· LOW grade path (pneumocystisis, fungi, multi-dermatomal zoster)
· Generally affect kids, but most common in HIV pts
· _ incidence of various malignancies, esp lymphomas
3. Soft tissue bacterial infections
· Gingivitis, lymphadenitis, osteomyelitis, pulmonary “cool” abscesses
· ~ always by 2 yrs, often from birth w/delayed separation of umbilical cord
· Typically infected w/low grade pathogens OR catalase + organisms (staph, strep, pseudomonas,
E. coli, candida, aspergillus)
4. Depends on complement (C) component defect:
· Early C defects _ respiratory infections, recurrent colds
· Late C defects _ gram- infections (recurrent meningitis)

X-linked Hypogammaglobulinemia (Bruton’s Agammaglobulinemia)

1. Congenital B cell deficiency

2. B cells don’t develop, atypical lymph node structure w/o germinal centers or plasma cells
3. Very low serum Igs of all isotypes
4. Most common defect is in “Bruton’s” tyrosine kinase/Btk
· Required for maturation of pre-B cells to mature B-cells

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· Seems to be imp for Ig light chain synthesis
5. Diagnosis: serum protein electrophoresis to exclude lymphoid/plasma cell malignancy,
quantitative Ig isotypes, flow cytometry using B cell markers (CD19 or CD20)
6. Treatment: g-globulin replacement (IV every 3-4 weeks)
· Antibiotic therapy of sinopulmonary infections

IgA deficiency

1. Most common congenital humoral immunodeficiency

· 1:700 of Caucasians from northern Europe background
2. Does NOT always cause disease (may be subclinical)
3. Variable inheritance w/autosomal dominant or recessive
4. May lead to common variable immunodeficiency
5. Clinical severity HIGHLY variable (many asymptomatic)
6. Others have serious, recurrent sinopulmonary and GI infections
7. B-lymphocyte number is NORMAL
8. LOW IgA
9. Same treatment as Bruton’s

Common variable immunodeficiency

1. Variable autosomal genetic mechanism, but develops in late childhood to early adult life (thus
an “acquired” ID)
2. Hyperplastic lymph nodes w/normal to increased numbers of B-cells but decrease in plasma
cells
3. Increase in lymphoid and GI malignancies as well as autoimmune diseases
4. VERY low IgG, low to NO IgA
5. Same treatment as Bruton’s

SCID

1. Heterogenous group of disorders w/defective development of both B- and T- cells, usually due
to abnormal development of bone marrow cells
2. In some forms, abnormal B-cells is secondary to dysregulation of abnormal T-cells
3. Thymus and peripheral lymph nodes do not develop
4. Affected pts usually die of infections w/in 1st year of life if condition is not recognized
5. Deficiency in IL-2 receptor for gamma chain
6. Can’t respond to IL-2, IL-4, IL-7
7. Treatment: bone marrow transplant (cure if successful)

1. Ataxia telangiectasia

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2. Wiskott-Aldrich
3. Mucocutaneous candidiasis

1. Aut recessive, mutation in DNA repair genes

· Child starts to walk, but then regresses (gets ataxic) @ 14-16 months, end up in wheelchair by
age 7-10
· Then develop telangiectasia of lateral aspect of eye
· Lymphopenia and IgA deficiency commonly occur
2. X-linked disease of T cell defect
· Recurrent pyogenic infections, eczema in weird places
3. Severe form of candida that spreads everywhere
· T cell defect where T cells don’t “see” candida
· Treatment: antifungals
· Survive to adulthood

DiGeorge Syndrome

1. Congenital defect of T cells of variable severity

2. Malformation of 3rd and 4th branchial clefts
3. Manifestations include:
· Thymic aplasia w/deficiency of T-cell development
· Absent parathyroids w/hypocalcemia
· Abnormality of great vessels connected to heart
· Facial deformities (wide set eyes, low set ears, “funny looking kid”/FLK)
4. Associated w/maternal alcohol ingestion, autosomal dominant inheritance, translocation of
chromosome 22
5. May improve w/time, probably due to partial thymic function or substitution of other lymph
tissue for thymus

Chronic granulomatous disease

1. Recurrent soft tissue abscesses

2. Rare disorder affecting 1:1,000,000 (2/3 are X-linked)
3. Recurrent bacterial and fungal infection (often w/organisms that are catalase positive), often
w/formation of granulomas
4. X-linked: defect in production of superoxide b/c of:
· Cytochrome b558 defect _ impaired NADPH oxidase
5. Autosomal: defect in other components of NAPDH oxidase
6. Diagnosis: CBC
· Nitroblue tetrazolium test or chemiluminescence to assess production of O2 radicals (dye
reduces to dark color by oxidation)
7. Treatment: IFNg

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Leukocyte adhesion defect

1. Extremely rare
2. Umbilical cords don’t separate, still present @6 months b/c neutrophils can’t go into that area
to lyse collagen to break it off
3. High white count (b/c neutrophils are staying in the blood and can’t find their way out)
4. Measure CD18 adhesion molecule to diagnose
· Absent in these pts

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