Chapter 5

DISEASES OF THE IMMUNE SYSTEM

Sr. No. TOPIC Page No.
1 Innate & Adaptive immunity 2

2 T-lymphocytes 2

3 B-lymphocytes 3

4 Dendritic cells 3

5 Natural killer (NK) cells 4

6 Hypersensitivity reaction 4

7 Type I Hypersensitivity reaction 5

8 Type II Hypersensitivity reaction 8

9 Type III Hypersensitivity reaction 10

10 Type IV Hypersensitivity reaction 11

11 Immunological tolerance 13

12 AIDS 15

13 Amyloidosis 20

14 Important questions 24

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 INNATE & ADAPTIVE IMMUNITY

The mechanisms of protection against infections fall into two broad categories.

Innate (natural/native) immunity

Refers to defense mechanisms that are present even before infection. Innate immunity is the first
line of defense.

Components of innate immunity:

1. epithelial barriers that block entry of microbes
2. phagocytic cells (mainly neutrophils and macrophages)
3. dendritic cells
4. natural killer (NK) cells
5. several plasma proteins, including complement system

Recognition of microbes:
Components of bacteria and viruses

Are recognized by epithelial cells and leukocytes through Toll-like receptors (TLRs) located on
their cell surface and in endosomes

Activated TLRs lead to activation of transcription factors, notably NF-κB (Nuclear Factor κB)

Begin phagocytosis

Adaptive (acquired/specific) immunity

consists of mechanisms of immune response that develop on exposure to microbes or
nonmicrobial substances. Adaptive immunity is more powerful than innate immunity.

Components of adaptive immunity:

1. lymphocytes

Types of adaptive immunity:

Humoral immunity, which protects against extracellular microbes and their toxins. It is mediated
by B (BM-derived) lymphocytes and their products, antibodies (Ig).

Cell-mediated (or cellular) immunity, which is responsible for defense against intracellular
microbes. It is mediated by T (thymus-derived) lymphocytes

T-LYMPHOCYTES

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Development

Develop from precursors in the thymus

Location of mature T cells

1. 90% of body’s 1012 T cells are found in T-cell zones of peripheral lymphoid organs
2. though only 10% T cells are found in blood, yet they constitute 60% to 70% of blood
lymphocytes

Types of T cells
T-cells differentiate into helper cells (CD4+), cytotoxic cells (CD8+), regulatory (CD4+,
CD25+) or memory cells.

CD4 and CD8 T-cells

CD4+ Helper T-cells CD8+ Cytotoxic/Killer T-cells

Expressed on 60% T-cells Expressed on 30% T cells
Help macrophages and B-lymphocytes to Function as cytotoxic (killer) T lymphocytes to
combat infection, thus called helper T cells. destroy host cells harboring microbes

Subsets:
1. TH1 cells: secrete cytokine IFN- γ, which is
a potent macrophage activator.
2. TH2 cells: produce IL-4, which stimulates
B cells to differentiate into IgE-secreting
plasma cells, and IL-5, which activates
eosinophils.
Bind to class II MHC molecules Bind to class I MHC molecules

Mechanism of action
Antigens that are displayed by major histocompatibility complex (MHC) molecules on the
surfaces of antigen-presenting cells (APCs) are recognized by antigen- specific T-cell receptor
(TCR).

B-LYMPHOCYTES

Development

Develop from precursors in bone marrow

Location of mature T cells

1. constitute 10% to 20% of blood lymphocytes
2. present in peripheral lymphoid tissues such as lymph nodes, spleen, and mucosa-
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 associated lymphoid tissues

Mechanism of action
IgM and IgD are the antigen-binding components of the B-cell receptor complex. B-cells
recognize antigens via this complex.

DENDRITIC CELLS

These cells have numerous fine cytoplasmic processes that resemble dendrites, from which they
derive their name.

Types of dendritic cells

1. Interdigitating dendritic cells or simply dendritic cells: are the most important antigen-
presenting cells (APCs) for T-cell. They are located under epithelia and in the interstitia
of all tissues. Immature dendritic cells within the epidermis are called Langerhans cells.
2. Follicular dendritic cell: present in the germinal centers of lymphoid follicles in the
spleen and lymph nodes

NATURAL KILLER (NK) CELLS

NK cells constitute 10% to 15% of blood lymphocytes. They are also called large granular
lymphocytes because they are:
1. larger than small lymphocytes
2. contain abundant azurophilic granules

Properties of NK cells

• Early line of defense: They have the ability to kill microbes and tumor cells, without prior
exposure to or activation by these microbes or tumors.
• Antibody-dependent cell- mediated cytotoxicity (ADCC): ADCC is a property of natural
killer (NK) cells. It is CD 16 positive. CD16 is Fc receptor for IgG. IgG-coated target
cells are lysed through this site.
• NK cells are CD56 positive.

HYPERSENSITIVITY REACTIONS

Type of Reaction Disorder
Type I hypersensitivity Anaphylaxis
(Immediate) Allergies
Bronchial asthma (atopic forms)
Type II hypersensitivity Autoimmune hemolytic anemia
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(Antibody-mediated) Autoimmune thrombocytopenic purpura
Goodpasture syndrome
Type III hypersensitivity SLE
(Immune complex–mediated) Some forms of glomerulonephritis
Serum sickness
Arthus reaction
Type IV hypersensitivity Contact dermatitis
[Cell-mediated (delayed)] Type I diabetes
Rheumatoid arthritis
Inflammatory bowel disease
Tuberculosis

TYPE 1 HYPERSENSITIVITY REACTION

Definition

Immediate, or type I, hypersensitivity is a rapid immunologic reaction occurring within minutes

after the combination of an antigen with antibody bound to mast cells in individuals previously
sensitized to the antigen. These reactions are also called allergy and antigen is called allergen.

They may manifest as a systemic disorder (anaphylaxis) or a local reaction [skin allergy, hives,
allergic rhinitis and conjunctivitis, hay fever, bronchial asthma, or allergic gastroenteritis (food
allergy)].

The term “atopy” refers to predisposition for development of localized immediate

hypersensitivity reactions to a variety of inhaled and ingested allergens; e.g. atopic asthma.
Atopic individuals have higher serum IgE levels and IL-4–producing TH2 cells. Immediate
hypersensitivity reactions triggered by temperature extremes and exercise, do not involve TH2
cells or IgE; such reactions are called “non-atopic allergy.”

Many local reactions show two phases:

1. Immediate or initial reaction: occurs within 5 to 30 minutes of exposure to an allergen
and subsides in 60 minutes. It is characterized by vasodilation, vascular leakage and
smooth muscle spasm or glandular secretions.
2. Late-phase reaction: occurs 2 to 24 hours later without additional exposure to antigen and
may last for several days. It is characterized by infiltration of inflammatory cells and
tissue damage.

Mechanism of action

Mast cells, TH2 cells and eosinophils play an important role in type-I hypersensitivity reactions.

Mast cells (Refer to the figure given below):

• derived from bone marrow
• widely distributed in the tissues- near blood vessels and nerves and in subepithelial
tissues
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• are activated by IgE, C5a and C3a, IL-8, drugs like morphine, physical agents like heat,
cold, sunlight
• have high-affinity receptor FcεRI for Fc portion of IgE
• when allergen binds to IgE attached to mast cell, it activates signal transduction pathways
• it leads to mast cell degranulation with release of preformed (primary) mediators
stored in the granules, and de novo synthesis and release of lipid (secondary) mediators.
They are responsible for the immediate phase reaction.
• Primary mediators can be grouped into three:
1. Vasoactive amines: histamine which causes smooth muscle contraction, increased
vascular permeability, and increased mucus secretion by nasal, bronchial, and
gastric glands.
2. Enzymes: proteases and hydrolases, which cause tissue damage and activation of
complement system
3. Proteoglycans: heparin and chondroitin sulfate
• Secondary mediators: mast cell activation leads to activation of phospholipase A2, which
acts on membrane phospholipids to yield:
1. arachidonic acid (AA): AA produce:
a) leukotrienes (LT): LT-C4 and -D4 are the most potent vasoactive and
spasmogenic agents, several thousand times more active than histamine. LT-
B4 is highly chemotactic.
b) prostaglandins (PG): PG-D2 causes bronchospasm and increased mucous
secretion
2. Platelet-activating factor (PAF): causes platelet aggregation, release of histamine,
bronchospasm, increased vascular permeability, and vasodilation
• Cytokines: mast cells contain cytokines. TNF, IL-1 and chemokines are responsible for
the late phase reaction, while IL-4 amplifies the TH2 response.

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TH2 cells:
Dendritic cells capture the antigen from its site of entry and present it to naïve CD4+ helper T
cells

In presence of IL-4, T cells differentiate into TH2 cells

TH2 cells in turn produce cytokines like IL-4, IL-5, and IL-13:
• IL-4 & IL-13 stimulate B cells to release IgE
• IL-5 activate eosinophils

Eosinophils:
• Epithelial cells, TH2 cells, and mast cells secrete chemokines, such as eotaxin
and others, which recruit eosinophils in the late phase of reaction.
• Survival of eosinophils in tissues is favored by IL-3, IL-5, and granulocyte-macrophage
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 colony-stimulating factor (GM-CSF)
• IL-5 is the most potent eosinophil-activating cytokine
• Activated eosinophils secrete:
a. proteolytic enzymes, major basic protein and eosinophil cationic protein, which are
toxic to epithelial cells
b. leukotriene C4 and PAF, which activate mast cells

Systemic Anaphylaxis

Cause
Exposure to even extremely small quantity of allergen can trigger anaphylaxis:
a. Hospital settings: administration of Ig, hormones, allergens in transfused blood, drugs
(e.g. penicillin)
b. Community setting: exposure to food allergens (e.g. peanuts, shellfish) or insect toxins
(e.g. bee venom)

Signs & symptoms

• itching, hives, and skin erythema appear within minutes of exposure

• followed by respiratory distress due to bronchospasm
• laryngeal edema results in hoarseness and further compromises breathing
• GIT symptoms include vomiting, abdominal cramps, diarrhea characterized by
• vascular shock, widespread edema
• shock and even death within an hour


TYPE II HYPERSENSITIVITY REACTION

Definition

Type II or antibody-mediated hypersensitivity is caused by antibodies that react with antigens

present on cell surfaces or in the extracellular matrix.

Mechanism of action
Antibody-mediated cell destruction occurs by:
1. Opsonization and phagocytosis
2. Antibody-dependent cellular cytotoxicity (ADCC)
3. Inflammation
4. Cellular dysfunction

Opsonization and phagocytosis:

• Cells opsonized by IgG antibodies: are recognized and phagocytized by phagocytes,
which have Fc receptors.
• Cells opsonized by complement products: Some cells may activate complement system
by the classical pathway. C3b and C4b thus produced get deposited on the cell surface.
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 Phagocytes, which have receptors for C3b and C4b recognize and phagocytize these
cells. Complement activation also disrupts cell membrane by “drilling holes” through the
lipid bilayer, thereby causing osmotic lysis of the cells.

Antibody-dependent cellular cytotoxicity (ADCC): Cells coated with low concentrations of IgG
antibody are killed by monocytes, neutrophils, eosinophils, and NK cells without phagocytosis.

Inflammation:
When antibodies deposit in fixed tissues, such as basement membranes and extracellular matrix,
the resultant injury is due to inflammation.

These antibodies activate complement.

C3a and C5a increase vascular permeability

C5a is chemotactic. Activation of leukocytes leads to release of inflammatory mediators like

prostaglandins and lysosomal enzymes

Antibody-mediated inflammation is the mechanism responsible for tissue injury in some forms
of glomerulonephritis and vascular rejection in organ grafts.

Cellular dysfunction:
In some cases, antibodies are directed against cell surface receptors, either impairing or
stimulating their function. Disease occurs without causing cell injury or inflammation.

E.g. in myasthenia gravis, patient develops antibodies against acetylcholine receptors in the
motor end plates of skeletal muscles, which block neuromuscular transmission, causing muscle
weakness.

In Graves disease, antibodies against TSH receptors on thyroid epithelial cells stimulate the cells,
resulting in hyperthyroidism.

Diseases caused due to type II hypersensitivity reaction

Diseases Target antigen

Autoimmune hemolytic anemia Rh blood group antigens, I antigen
Rh hemolytic disease of newborn Rh blood group antigens
Autoimmune thrombocytopenic purpura Platelet membrane proteins
Pemphigus vulgaris Epidermal cadherin (intercellular junction
proteins)
Vasculitis caused by ANCA Neutrophil granule proteins
Goodpasture syndrome Basement membrane proteins present in kidney
glomeruli and lung alveoli
Acute rheumatic fever Streptococcal cell wall antigen
Myasthenia gravis Acetylcholine receptor
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Graves disease (hyperthyroidism) TSH receptor
Insulin-resistant diabetes Insulin receptor
Pernicious anemia Intrinsic factor of gastric parietal cells

TYPE III HYPERSENSITIVITY REACTION

Definition

Type III or immune complex-mediated hypersensitivity occurs when antigen-antibody

complexes produce tissue damage by eliciting inflammation at the sites of deposition. Antigens
can be exogenous (foreign protein or microbe) or endogenous (autoimmunity).

Type III hypersensitivity reaction can be systemic or local.

Mechanism of action
There are two types of immune complexes:
1. Circulating immune complexes: where antigen combines with antibody within the
circulation and the complex gets deposited in vessel walls.
2. In-situ immune complexes: complex is formed at extravascular sites where antigen is
“planted”.

Pathogenesis of systemic immune complex disease is divided into three phases:

1. Formation of immune complexes in circulation: antibodies are formed within a week of
injection of antigens. The antibodies bind with antigens still present in blood to form
circulating immune complexes.
2. Deposition of complexes in various tissues: Organs where blood is filtered at high
pressure to form other fluids, like urine and synovial fluid, are favored sites; hence,
immune complexes frequently deposit in glomeruli and joints.
3. Tissue injury by immune complexes: Once complexes are deposited in the tissues, they
initiate an acute inflammatory reaction. This occurs approximately ten days after
administration of antigen. Patient presents with fever, urticaria, joint pains, lymph node
enlargement, and proteinuria. Complement-fixing antibodies (IgG and IgM) and
antibodies that bind to leukocyte Fc receptors (some IgG) produce pathologic lesions of
immune complex disorders.

Morphology

• Disorder is characterized by acute necrotizing vasculitis (necrosis of the vessel wall and
intense neutrophilic infiltration).
• Necrotic tissue and deposits of immune complexes, complement, and plasma protein
produce a smudgy eosinophilic deposit that obscures the underlying cellular detail, called
fibrinoid necrosis.
• When deposited in the kidney, the complexes can be seen by immunofluorescence
microscopy as granular lumps or by electron microscopy as electron-dense deposits along
the glomerular basement membrane.

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Diseases caused due to type III hypersensitivity reaction

Diseases Target antigen

SLE Nuclear antigen
Poststreptococcal Streptococcal cell wall antigens planted in glomerular BM
glomerulonephritis
Polyarteritis nodosa HBV in some cases
Reactive arthritis Bacterial antigens, e.g. Yersinia
Serum sickness Systemic disease occurs when large amounts of foreign
serum (e.g. horse globulin) are administered. However, this
is uncommon in modern times.
Arthus reaction (experimental) localized form of reaction usually elicited in the skin

TYPE IV HYPERSENSITIVITY REACTION

Definition

Type IV cell-mediated or delayed hypersensitivity reaction is initiated by antigen-activated T

lymphocytes, including CD4+ and CD8+ T cells. The antigens could be environmental or self-
antigens. CD4+ T cells are the dominant cells in most type IV reactions, while CD8+ T cells
dominate in viral infections, graft and tumor rejection and type-1 diabetes.

Reactions of CD4+ T Cells

The reaction can be divided into following phases:

Proliferation of CD4+ T cells: Naive CD4+ T cells recognize antigens presented by antigen
presenting cells (APC- dendritic cells and macrophages) and secrete IL-2, which functions as an
autocrine growth factor, leading to proliferation of T-cells.

Differentiation of CD4+ T cells:

CD4+ T cells

In presence of IL-12 produced by APC In presence of IL-1, -6, -23 produced by APC
& transforming growth factor-β (TGF-β) by
many cell types

CD4+ T cells differentiate into TH1 cells CD4+ T cells differentiate into TH17 cells

Differentiated cells enter circulation and remain in memory pool for long.

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Responses of differentiated cells:
Upon repeat exposure to the same antigen, T cells recognize the antigen and respond.

TH1 cells secrete IFN-γ, which in turn activate macrophages. IFN-γ activated macrophages have
following effects:
1. express more class II MHC molecules on the surface facilitating further antigen
presentation
2. secrete TNF, IL-1, and chemokines, which augment phagocytosis and kill microbial
killing
3. produce more IL-12, thereby amplifying the TH1 response

TH17 cells have following effect:

1. they secrete IL-17, IL-22, chemokines, and other cytokines, which recruit neutrophils and
monocytes
2. they produce IL-21, which amplifies the TH17 response

Reactions of CD8+ T Cells

• CD8+ T cells contain preformed mediators- perforin, granzymes and serglycin in their
lysosome-like granules, which enter target cells by endocytosis.
• Within target cell cytoplasm, perforin releases granzymes from the complex.
• Granzymes activates caspases, which induces apoptosis of the target cells.
• Activated CD8+ T cells also express Fas ligand, which bind to Fas expressed on target
cells and trigger apoptosis.
• Activated CD8+ T cells also produce IFN-γ, thus producing inflammatory reaction.

Morphology

Characterized by accumulation of mononuclear cells, mainly CD4+ T cells and macrophages,

around venules, producing perivascular “cuffing”.

With certain persistent or nondegradable antigens, such as tubercle bacilli, activated

macrophages undergo morphologic transformation into epithelium-like cells and are called
epithelioid cells. Aggregation of epithelioid cells, surrounded by a collar of lymphocytes, is
called granuloma.

Diseases caused due to type IV hypersensitivity reaction

Diseases Target antigen

Type I diabetes
Multiple sclerosis
Rheumatoid arthritis
Crohn’s disease
Peripheral neuropathy
Guillain-Barre syndrome ?
Contact dermatitis
Tuberculosis
Antigens of pancreatic islet cells
Protein antigens in CNS myelin
? type II collagen
Commensal bacteria
Protein antigens of peripheral nerve
Myelin
Various environmental antigens (poison ivy or poison oak)
Mycobacterium TB
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Tuberculin reaction Purified protein derivative (PPD)

IMMUNOLOGICAL TOLERANCE

Definition
Immunological tolerance is the failure to mount an immune response to an antigen. It could be
natural or self-tolerance, which refers to lack of responsiveness to individual's own antigens.
Self-tolerance is classified into central tolerance [occurring in thymus and bone marrow (BM)]
and peripheral tolerance (occurring in peripheral lymphoid tissue).

Developing/immature T/B cells could belong to self-reactive clone or non-self reactive clone.
Self-reactive clones are rendered harmless by mechanisms of self-tolerance, while non-self
reactive clones induce immunity.

Mechanism of immunological tolerance
Immunological tolerance

Central tolerance Peripheral tolerance

T-cell B-cell
Anergy

Negative selection Receptor editing

or deletion

Suppression by regulatory T-cells

(associated with both central & peripheral tolerance)

These self-reactive clones are then removed by “activation-induced cell death”

through mechanism of apoptosis

Central Tolerance

In this, developing/immature T- and B-lymphocytes in the central lymphoid organs (thymus for
T cells and BM for B cells) that recognize self-antigens are killed or rendered harmless.
Mechanism of central tolerance:

• Central T-cell tolerance: Developing/immature T-cells have high-affinity receptors for

self-antigens. They encounter central as well as some peripheral self-antigens in the
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 thymus. Protein autoimmune regulator (AIRE) stimulates expression of some peripheral
self-antigens in the thymus. When developing T-cells encounter a self-antigen in the
thymus, they are killed by apoptosis. This process, called negative selection or deletion,
is responsible for eliminating many self-reactive lymphocytes from the T-cell pool.

• Central B-cell tolerance: When developing B cells recognize self-antigens in the bone
marrow, many of them reactivate antigen receptor gene rearrangement and begin to
express new antigen receptors, not specific for self-antigens. This process is called
receptor editing. If receptor editing does not occur, the self-reactive cells undergo
apoptosis.

Not all self-antigens are present in thymus and BM. Thus self-reactive lymphocytes that escape
negative selection need to be deleted in peripheral tissues.

Peripheral tolerance

Anergy of mature T cells: This refers to prolonged or irreversible functional inactivation of

mature lymphocytes in the peripheral tissue, when they encounter self-antigens.

Activation of T cells requires two signals (refer to the figure below):

1. TCR recognize peptide antigen presented to them by APCs through the latter’s MHC
molecules
2. APCs should also contain “second/costimulatory signals”- B7 on their cell surface, which
bind to CD28 present on T cells

If antigen is presented by APCs that do not bear the costimulators a negative signal is delivered,
and the T-cell becomes anergic.

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Two mechanisms of T-cell anergy are:
1. Cells lose their ability to trigger biochemical signals from the TCR complex, because of
proteolytic degradation of receptor-associated signaling proteins
2. Receptor CTLA-4/PD-1 structurally similar to CD28, compete with CD28 to bind to B7
molecules on APC, sending inhibitory signals and rendering T-cell anergic

Anergy of mature B cells: Anergy also affects mature B cells in peripheral tissues when they
encounter self- antigen.

Suppression by regulatory T cells

Regulatory T cells develop mainly in the thymus, but they may also be induced in peripheral
lymphoid tissues. Regulatory T cells are CD4+ T cells that express CD25, α-chain of IL-2
receptor, and transcription factor Foxp3. The inhibitory activity of these cells is mediated by
secretion of immunosuppressive cytokines such as IL-10 and TGF-β.

Deletion by activation-induced cell death

CD4+ T cells that recognize self-antigens receive signals that promote their death by apoptosis.
This process is called activation-induced cell death. Two mechanisms proposed are:

1. T cells that recognize self-antigens, express pro-apoptotic gene of Bcl family- Bim and
down regulate expression of anti-apoptotic genes Bcl-2 and Bcl-x. Unopposed Bim
triggers apoptosis by the mitochondrial pathway.
2. Lymphocytes express Fas (CD95). FasL is expressed on activated T lymphocytes. The
engagement of Fas by FasL induces apoptosis by the death receptor pathway. Self-
reactive B cells may also be deleted by FasL on T cells.

Some antigens are hidden (sequestered) from the immune system, because the tissues in which
these antigens are located do not communicate with blood or lymph. Thus, self-antigens in these
tissues do not induce tolerance but fail to elicit immune responses. This is true for testis, eye, and
brain, and these sites are called immune-privileged sites.

AIDS

Routes of transmission

1. Sexual (homo-/hetero-sexual) transmission: Viral transmission through this route occurs
in two ways:
a. direct inoculation into the blood vessels breached by trauma
b. infection of dendritic cells or CD4+ cells within the mucosa
Sexual transmission of HIV is enhanced by coexisting sexually transmitted diseases like
syphilis, chancroid, herpes, gonorrhea and chlamydia.
2. Parenteral transmission of HIV: occurs in intravenous drug abusers, hemophiliacs who
receive factor VIII and factor IX concentrates, and random recipients of blood

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 transfusion.
3. Mother-to-infant transmission: Infected mother can transmit HIV to baby by three routes:
a. in utero by transplacental spread
b. during delivery through an infected birth canal
c. after birth by ingestion of breast milk
Administration of antiretroviral therapy to infected pregnant mother can eliminate
mother-to-child HIV transmission.
4. Transmission of HIV infection to health care workers: there is an extremely small but
definite risk. Seroconversion has been documented after accidental needle-stick injury or
exposure of non-intact skin to infected blood in hospitals. After needle- stick accidents,
the risk of seroconversion is 0.3%, and antiretroviral therapy given within 24 to 48 hours
of a needle stick reduces the risk eightfold times.

HIV infection does not get transmitted by casual personal contact in the household, workplace,
or school. Spread by insect bites is virtually impossible.

Structure of HIV
• Spherical in shape
• Contains electron-dense core surrounded by lipid envelope
• Core contains:
1. capsid protein p24
2. nucleocapsid protein p7/p9
3. two copies of RNA
4. three enzymes (protease, reverse transcriptase, and integrase)
• Core is surrounded by matrix protein p17, which lies underneath the envelope
• Envelope is studded with glycoproteins, gp120 and gp41
• HIV-1 RNA genome contains the gag, pol, and env genes, and several other accessory
genes, including tat, rev, vif, nef, vpr, and vpu.

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 Lifecycle/ Pathogenesis of HIV

The life cycle of HIV consists of infection of host CD+ T cells, viral replication, and release of
virus and T cell immunodeficiency. Other cells, which are infected are macrophages and
dendritic cells.

HIV Infection of CD4+ T host cells

• HIV infects activated T cells, memory T cells but not naïve (unactivated) T cells. Naïve
cells consist of enzyme APOBEC3G, which introduces mutations in HIV genome,
inhibiting it’s replication.
• The initial step in infection is the binding of the gp120 envelope glycoprotein to CD4
molecules of T-cells.
• Binding to CD4 is not sufficient; HIV should also bind to coreceptors like CCR5 or
CXCR4 or both (dual-tropic).
• This results in exposure of hydrophobic region at the tip of gp41 called fusion peptide.
Fusion peptide inserts into the cell membrane of target cells, leading to fusion of the virus
with the host cell.
• After fusion the virus core enters the cytoplasm of the cell.

Viral replication

• Once internalized, RNA of the virus undergoes reverse transcription, leading to synthesis
of double-stranded complementary DNA (cDNA or proviral DNA).
• In quiescent T cells, HIV cDNA remain in the cytoplasm of host cell in linear form for
months or years, which accounts for latent HIV infection.
• Viral replication can take place only in activated T cells. A latently infected quiescent T-
cell gets activated on encounter with an environmental antigen. Activated T cells
upregulate transcription factors like NF-κB. Proviral DNA have NF-κB-binding sites.
Induction of NF-κB in such a cell (a physiologic response) activates transcription of HIV
proviral DNA (a pathologic outcome) and leads to production of virions.

Release of virus and T-cell immunodeficiency

• Viral particles bud from the host cell membrane. Extensive viral budding leads to death
of infected cell and release of virus. Mechanisms by which the virus directly kills
infected cells include:
1. increased plasma membrane permeability associated with budding of virus particles
2. virus replication interfering with protein synthesis
• Loss of CD4+ T cells is mainly because of the direct cytopathic effects of the replicating
virus. As the disease progresses, renewal of CD4+ T cells cannot keep up with the loss of
these cells. Marked reduction in CD4+ T cells, a hallmark of AIDS.
• HIV infection is also associated with qualitative defects in T cells:
1. reduction in antigen-induced T-cell proliferation
2. decrease in TH1-type responses relative to the TH2 type. Loss of TH1 responses
results in profound deficiency in cell-mediated immunity, leading to increased
susceptibility to infections by viruses and other microbes.
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 While loss of memory CD4+ helper T cells results in poor immune response to
previously encountered antigens.
• Because a subset of CD4+ T cells are memory T cells, which are long-lived (months to
years), they act as reservoirs of virus.

HIV Infection of Non-T cells

Infection of macrophages and dendritic cells is also important in the pathogenesis of HIV
infection:
• Majority of macrophages that are infected by HIV are found in tissues; fewer in blood
monocytes. But blood monocytes serve as vehicles for HIV transportation to various
organs.
• HIV-1 can multiply in terminally differentiated non-dividing macrophages by the
property of its ‘vpr’ gene.
• Macrophages are quite resistant to the cytopathic effects of HIV. Thus they serve as
reservoirs of infection, and are called ‘gatekeepers of HIV infection’.
• Two types of dendritic cells are important in pathogenesis of HIV- mucosal and follicular
dendritic cells present in germinal centers of lymph nodes. Mucosal dendritic cells
transfer virus to regional lymph nodes, where they infect CD4+ T cells. Most virions are
trapped in the dendritic processes of follicular dendritic cells, and are coated with anti-
HIV antibodies. Thus follicular dendritic cells serve as potential reservoirs of HIV.

HIV patients also display B-cell dysfunction suppressing humoral immunity.

Pathogenesis of CNS involvement

In addition to the lymphoid system, the nervous system is a major target of HIV infection. HIV is
carried to the brain by infected blood monocytes. They in turn infect macrophages and microglia
of CNS. Neurons are not infected. The profound neurologic deficit seen in HIV patients can be
attributed to damage by soluble factors (IL-1, TNF, IL-6) released from infected macrophages
and microglia.


Natural History of HIV Infection

Acute retroviral syndrome
40-90% of infected patients develop viral syndrome, which occurs 3 to 6 weeks after infection,
and resolves spontaneously in 2 to 4 weeks. Clinically, it is a self-limited acute illness with
nonspecific symptoms like sore throat, myalgias, fever, weight loss, and fatigue. Other clinical
features include rash, cervical adenopathy, diarrhea, and vomiting.

Mucosal dendritic cells in epithelia at sites of virus entry capture the virus and then migrate into
mucosal lymphoid tissues/ lymph nodes where they infect memory CD4+ T cells. Within days
after the exposure to HIV, virus replicates in the lymph nodes and leads to viremia. Through
blood virus disseminates throughout the body. This is the time when individual presents with

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symptoms of acute retroviral syndrome.

As infection spreads, individual mounts anti-viral humoral and cell-mediated immune responses,
evidenced by seroconversion (development of anti-viral antibodies within 3 to 7 weeks of
exposure). Development of virus-specific CD8+ cytotoxic T cells results in fall of viral titers and
containment of infection.

The viral load at the end of the acute phase reflects the equilibrium reached between the virus
and the host response. Extent of viremia, measured as HIV-1 RNA level at the end of acute
phase (called viral “set point”) is a useful surrogate marker of HIV disease progression. More the
viral load, poorer is the prognosis.

CD4+ cell counts are however more reliable markers for clinical management than viral load.
Centers for Disease Control (CDC) classification of HIV infection stratifies patients into three
categories on the basis of CD4+ cell counts:

Category 1 ≥500 CD4+ T cells/µL

Category 2 200 to 499 cells/µL
Category 3 ≤200 cells/µL

Chronic infection (phase of clinical latency)

During this period, patients are either asymptomatic or develop minor opportunistic infections,
like oral candidiasis (thrush), vaginal candidiasis, or herpes zoster. Mycobacterial tuberculosis is
seen in resource-poor regions. Some may develop autoimmune thrombocytopenia.

Lymph nodes and the spleen are sites of continuous HIV replication and T cell destruction.
CD4+ T cells can be replaced almost as quickly as they are destroyed. However, over a period of
years, there is rise in viral load with concurrent steady decline in the number of CD4+ T cells.
This is attributed to:
1. down-regulation of class I MHC molecules on infected cells so that viral antigens are not
recognized by CD8+ CTLs
2. evolution of virus, switching from CCR5 to enter its target cells to CXCR4 or both. This
coreceptor switch is associated with more rapid viral replication and CD4+ T-cell death.

AIDS

After a variable period of clinical latency, serious opportunistic infections, secondary neoplasms,
or clinical neurologic disease develop and the patient is said to have AIDS. The course of the
disease has been greatly modified due to the advent of highly active antiretroviral therapy
(HAART).

In the absence of treatment, most but not all patients with HIV infection progress to AIDS after a
chronic phase lasting from 7 to 10 years.

In rapid progressors, chronic phase lasts for 2 to 3 years.

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Long-term nonprogressors are untreated HIV-1–infected individuals who remain asymptomatic
for 10 years or more, with stable CD4+ T-cell counts and low levels of plasma viremia (<500
viral RNA copies/mL). They account for 5-15% infected individuals.

Elite controllers have undetectable plasma virus (50–75 viral RNA copies/mL). They account for
1% of infected individuals.

Table: Opportunistic infections, secondary neoplasms and neurological disease in AIDS

OPPORTUNISTIC INFECTIONS:
PROTOZOAL AND HELMINTHIC BACTERIAL INFECTIONS
INFECTIONS Atypical TB due to M. avium
Cryptosporidiosis Disseminated, pulmonary or extrapulmonary
Toxoplasmosis tuberculosis due to M. TB

FUNGAL INFECTIONS VIRAL INFECTIONS

Pneumocystosis Cytomegalovirus
Candidiasis Herpes simplex virus
Cryptococcosis Varicella-zoster virus
Coccidioidomycosis
Histoplasmosis
SECONDARY NEOPLASMS
(seen in 25-40% untreated patients. Most are caused by oncogenic DNA viruses)
Kaposi sarcoma (herpes) Cervical cancer in women (HPV)
Non-Hodgkin B-cell lymphoma (EBV) Anal cancer in men (HPV)
NEUROLOGICAL DISEASES
Aseptic meningitis Peripheral neuropathies
Vacuolar myelopathy Progressive encephalopathy designated
clinically as the AIDS-dementia complex

AMYLOIDOSIS

Definition

Amyloid is a pathologic proteinaceous substance, deposited in the extracellular space in various

tissues and organs of the body.

Properties of amyloid protein

Physical nature of amyloid:

• Electron microscopy: amyloid protein is seen as continuous, nonbranching fibrils of 7.5
to 10 nm diameter
• X-ray crystallography and infrared spectroscopy: amyloid proteins show characteristic
cross-beta- pleated sheet configuration

Chemical nature of amyloid:

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 1. Fibril proteins: constitute 95% of amyloid proteins. There are 20 fibril proteins, out of
which three and few other important proteins are mentioned below:
a. AL (amyloid light chain): derived from Ig light chains produced in plasma cells.
Its deposition is associated with certain forms of plasma cell tumors. Most AL
proteins are composed of λ light chains or their fragments, some of κ chains.
b. AA (amyloid-associated): it is a non-Ig protein synthesized in liver from precursor
serum amyloid-associated protein (SAA). AA has molecular weight of 8600 and
consists of 76 amino acid residues. Production of SAA protein is increased in
inflammatory states as part of the “acute phase response”; therefore, this form of
amyloidosis is associated with chronic inflammation, and is called secondary
amyloidosis.
c. Aβ amyloid: is found in the cerebral lesions of Alzheimer disease
d. Transthyretin (TTR): is a normal serum protein that binds and transports
thyroxine and retinol. In it’s normal form, TTR may be deposited in the heart of
aged individuals (called senile systemic amyloidosis). It’s mutant form is
associated with familial amyloid polyneuropathies.
e. β2-microglobulin: is a normal serum protein, which is a component of MHC class
I molecules. Its amyloid fibril subunit (Aβ2m) is associated with amyloidosis in
long-term hemodialysis patients.
f. Misfolder prion proteins: is seen in few cases of prion disease affecting CNS.
Therefore, prion diseases are sometimes considered examples of local
amyloidosis.

2. Serum amyloid P protein, proteoglycans and other glycoproteins: account for 5% of

amyloid proteins

Pathogenesis
Amyloidosis results from

Abnormal folding (misfolding) of proteins

Such misfolded proteins are produced either from normal proteins, when secreted in increased
amounts, or from mutant proteins

Misfolded proteins are normally degraded either intracellularly in proteasomes or extracellularly

by macrophages

Some misfolded proteins resist degradation, either due to enzyme defect or structural
abnormality

Such misfolded proteins are unstable and have tendency to self-associate (aggregate)

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These insoluble amyloid proteins get deposited in extracellular tissues and disrupt normal
functioning of tissue

Classification of amyloidosis

Clinicopathologic Category Associated Diseases Major Protein

SYSTEMIC (GENERALIZED) AMYLOIDOSIS
Primary amyloidosis
(associated with poor prognosis; Multiple myeloma or other form of
AL
median survival 2 years; less in plasma cell dyscrasia
multiple myeloma)
Chronic inflammatory conditions like
rheumatoid arthritis, ankylosing
spondylitis, inflammatory bowel
Secondary amyloidosis AA
disease- Crohn disease and ulcerative
colitis, heroin abusers, renal cell
carcinoma and Hodgkin lymphoma
Hemodialysis-associated
Aβ2m; this protein is
amyloidosis for over 20 years
Chronic renal failure not filtered through
(amyloid is deposited in synovium,
dialysis membranes
joints or tendon shealths)
HEREDITARY AMYLOIDOSIS
Familial Mediterranean fever
AA
(an autoinflammatory syndrome)
Familial amyloidotic neuropathies ATTR
Systemic senile amyloidosis (seen in
70-80s; commonly deposits in heart
ATTR
leading to restrictive
cardiomyopathy and arrhythmias)
LOCALIZED AMYLOIDOSIS
Senile cerebral Alzheimer disease Aβ
Endocrine amyloid:
Medullary carcinoma of thyroid A Calcitonin
Islets of Langerhans Type 2 diabetes AIAPP*
Isolated atrial amyloidosis AANF**

AIAPP*: Islet amyloid peptide

AANF**: Amyloid atrial natriuretic factor

Diagnosis
In suspected cases of primary amyloidosis, do:
1. serum and urine protein electrophoresis
2. Bone marrow aspirates show evidence of multiple myeloma or monoclonal plasmacytosis
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 3. Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid, specific
and quantitative test, used for follow-up in patients on treatment

Tissue diagnosis
Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid are commonly involved

Macroscopically:
Affected organ is enlarged, firm and has waxy appearance

Painting the cut surface with iodine imparts a yellow color that is transformed to blue violet after
application of sulfuric acid.

Microscopically:
Diagnosis of amyloidosis depends on the histologic demonstration of amyloid deposits in tissues.
The most common sites biopsied are the kidney, when renal manifestations are present, or rectal/
gingival/ abdominal fat tissues in patients suspected of systemic amyloidosis.

Staining characteristics of amyloid are:

• H&E stain: amyloid appears as an amorphous, eosinophilic, hyaline, extracellular
substance
• Congo red stain: imparts pink or red color
• Polarizing microscopy: green birefringence

Kidney

Most common and serious form of organ involvement

Grossly: normal size and color, or shrunken in advanced cases

Histologically: amyloid is deposited

• in the glomeruli as mesangial matrix thickenings
• along basement membranes causing capillary narrowing
• in interstitial peritubular tissue, arteries, and arterioles

Spleen
Moderate to marked splenomegaly (up to 800 gm)
Shows 2 patterns:
1. Sago spleen: amyloid deposits in white pulp, producing tapioca-like granule appearance
grossly. Fusion of the deposits gives rise to large, map-like areas of amyloidosis called
Lardaceous spleen.
2. Other pattern: amyloid deposits in red pulp, in the walls of the splenic sinuses and
connective tissue

Heart
Major organ involved in senile systemic amyloidosis.
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Grossly: enlarged and firm
Histologically:
• focal subendocardial accumulations- leading to damage of conduction system
• accumulations between the muscle fibers- may cause pressure atrophy

IMPORTANT QUESTIONS

SHORT NOTES

1. Type IV hypersensitivity reactions

2. Natural history of HIV infection
3. Etiopathogenesis of AIDS
4. Clonal anergy of lymphocytes
5. Sago spleen

SHORT ANSWERS

1. Name two opportunistic infections in AIDS.

Ans. Candidiasis, Cryptosporidiosis, Toxoplasmosis
2. Give two diseases caused by type II hypersensitivity reaction.
Ans. Autoimmune hemolytic anemia, Autoimmune thrombocytopenic purpura,
Goodpasture syndrome
3. Enumerate two stains for identification of amyloid.
Ans. Congo red imparts pink or red color to amyloid proteins
Green birefringence by polarizing microscopy
4. Functions of CD4+ T-lymphocytes
Ans. TH1 cells: secrete cytokine IFN- γ, which is a potent macrophage activator.
TH2 cells: produce IL-4, which stimulates B cells to differentiate into IgE-secreting
plasma cells, and IL-5, which activates eosinophils.
5. Antibody dependent cell-mediated cytotoxic reactions (ADCC)
Ans. Antibody-dependent cell- mediated cytotoxicity (ADCC) is a property of natural killer
(NK) cells. It is CD 16 positive. CD16 is Fc receptor for IgG. IgG-coated target cells are
lysed through this site.

The End

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