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Normal Host Defense and Primary Immunodeficiency

Janet Wong, M.D.

Functions of the Vertebrate Immune System Our immune systems need to be able to discriminate between self and
foreign in a way that allows it to exclude, eliminate or kill the foreign
invader. Any deficits in these functions will result in either an increased
frequency or severity of infections, that essentially produce disease in
€ Discriminate between self and foreign
otherwise healthy individuals. If the organism is able to get past the native
€ Exclude, eliminate or kill foreign invasion immune, and the native immune first exists in the absence of previous

€ Develop memory and amplified recall response exposure to the organism. Infection can occur, but the disease will not
occur because the immune system suppresses the growth prior to that.
€ Deficits result in
Disease occurs if the tempo of replication is faster, but yet allows the
• Increased frequency or severity of infections with pathogens immune system to catch up, and then severe fatal infection occurs in a
• Infections with nonpathogenic, opportunistic organisms situation where the organism is able to replicate more rapidly than the
immune response. And of course this can happen in one of two ways;
either the organism is very rapidly growing, or the immune system is slow
in responding, and of course if you have an inadequate immune system.

Components of Innate (Preexisting) Immunity
And our phagocytes, which of course we routinely end up knocking these
out in cancer chemotherapy and other sorts of interventions that are being
€ Barriers - skin and mucus membranes, normal flora, spleen
performed in trying to help patients. So the phagocytic cells included of
€ Opsonins - complement, collectins, CRP course are neutrophils and monocytes in the blood, active follicles in the

€ Phagocytes - neutrophils, monocytes, macrophages and NK cells tissues. These cells of course regularly protect us initially from viruses,
primarily in the absence of prior increase in the antigens specific immunity.

What are the components of antigens specific immunity? While these are
becoming the illustrated test to find HIV, The C4 T-cells are particularly
important because they are sort of the regulators of everything else. They
set the tempo for the whole immune response, that of rest of the antigens
specific system. They do it by secreting proteins called cytokines. In
addition to secreting cytokines, they have proteins that are expressed on the
membrane when they are activated by a form of antigen, and these proteins
help enhance the recognition phase of the immune response, by including
antigen presenting subfunction, and also act on B cells. And finally there
are B cells and antibodies of course that protect us from bacterial
pathogens, especially capsular pathogens, but in addition, play an
important role in protecting us against a wide variety of things, such as viral
infections and so forth.

The patient presents to you with a clinical problem, usually infection,

sometimes odd immunity, sometimes malignancy, and you must try to
figure out what is going on. So, your looking at infections that are associ-
ated with or patients that present with recurring or persistent sign of
pulmonary or ear infections, I usually like to break them down into two
groups. If they occur without GI infections, the most common deficits are
deficits in innate respiratory mucosal defenses. Allergies were secondarily
affects of the defenses, or deficits in humoral immunity, that is antibody
production in particular. If there are also GI type of infections, than antibody
deficiencies becomes even the more vital. So what are the components of
the innate defenses that are intrinsic to our respiratory tract. We do not get
many humans that have this deficiency. And then finally, macrophages in
the lung, and those play a primary role in clearing microbes in the first
patch effect, and also in secreting cytokines that were recruited for other
intentions. Well the most common one I will refer to is unfavorable
anatomy. Occurring in the first year or two of life. In other situations,
secondary to infection, or other anatomical abnormalities such as we seen
in individuals with cleft palate and lip, you may have difficulty with normal
cleft, because of unfavorable anatomy. And then of course there are
secondary or primary cellular dysfunction. Secondary being overwhelmingly
the more common, and usually being secondary to prior infections. So the
ciliated cells don’t function normally. That is commonly associated with
cystic fibrosis. So that is a rare immune deficiency localized in the
respiratory tree, that is usually on the bottom of our evaluation list.

So how does one go about evaluating these children who have recurrent
infections in the sinus and ears. After you take the history, evaluate the
patient, and do a radiograph of the sinuses and of the chest, looking for
abnormalities. Screening allergy evaluation generally to those, the second
part of that is a good history and family history. Swab tests of course is
straightforward, easy, and a part of the evaluation. Ancillary evaluation may
occur except in those cases where we have exhausted other possibilities,
and this means obtaining ciliated cells from the nose, or the bronchial tree.
The problem here is you have to get it from a noninflamed area, because

Components of Antigen-specific Immunity otherwise you will be looking at the secondary abnormality.

Humoral immunity. This is most likely to be a problem in individuals who

have recurrent respiratory tract infections, particularly associated with GI
€ CD4 T cells (helper/master control)
tract infections. There are four basic classes of antibody: M, G, A and E. In
€ Cytokines -IL-2, IFN-( TNF-a/IL-4, IL-5 antibody G there are four subclasses. It is in your primary response to

€ Cognate help for APC/B cells via CD40 ligand immunization, typically produce predominantly IgM, and subsequently one
switches to making IgG and/or IgA. The basis of that switch is distributed
€ CD8 and 75 T Cells
by T-cells, but the essence of that observation is that if one had the deficit
• Cytotoxicity of T-cell function, one will have the deficit in the antibody production,
• Cytokines because of the problem of switching from IgM to IgG, and of making high-
dependent antibodies which are also dependable. The major mucosal
€ B cells and antibody
humoral defenses are the secretory IgA. There are two subclasses, the only
thing we’re doing about that, is that the secretions that are approximately
a quarter of analysis of two subclasses as opposed to one, is almost all IgA
1. So it’s useful to have it in the secretion since it is more likely to remain
intact than those organisms around. IgA is absent from the secretions at
birth, it appears about a month at life and reaches out about six to eight
years of life. So again the baby is born without good mucosal senses. And
probably we’re saying here that IgA deficiency is almost always detectable
in the blood. There are extremely rare cases where the deficit is only
manifested in the secretions. But for all intents and purposes, one needn’t
collect secretions to evaluate the patient for IG deficiencies, one can check
it out in the blood.

Recurrent/Persistent Sinopulmonary and Ear
Infections When to suspect primary immunoglobulin or antibody deficiency. Well, it’s
when ear and sinus infections are more common than in the general
population, and without other explanation. Especially if associated with
€ Without GI Infections
recurrent pneumonias. Of course if you have GI infections or viral patho-
• Suspect deficit in innate, respiratory mucosal defenses, allergy gens, that should raise your level of concern for an underlying humoral

or humoral immunity immune deficiency. I have listed some data here from a report a few years
back on the frequency of otitis, and so forth, and as you all know it is
€ With GI Infections
extremely common. So otitis would not raise a big red flag. If it appeared in
• Suspect antibody deficiency other things, one may need to find suspicious, and begin to evaluate for
humoral immune deficiency, which we will talk about in a moment.

Intrinsic Defenses of the Respiratory Mu-
cosa/Lung So what are the danger in immunodeficiencies associated with a primary
deficit in the antibody production? Well there are two major X-linked
immune deficiencies. X-linked agammaglobulinemia, or
hypogammaglobulinemia, and the X-linked hyper IgM syndrome. These
€ Normal Epithelial Structure/Function
conditions almost always present within the first two years of life, but like
• Mucociliary clearance all humoral immune deficiency, rarely presents before four to six months of

• Antimicrobial activity life, because of the presence of maternal antibodies, subserving the
function that the wholesome antibody would ordinarily survive. So again,
1. Pro/Anti inflammatory Cytokine Production
under six months of age, it is unlikely, it is usually by three or four months
2. Opsonins - surfactant apoprotein A of age that you might have problems in immune deficiencies. Common

• Alveolar Macrophages variable immune deficiency remains such at all. It is common heteroge-
neous, and is onset earlier. About half the patients present first in
1. Antimicrobial activity
adulthood, and it is the most common immunodeficiency. IgA deficiency
2. Pro/Anti Inflammatory/Cytokine Production occurs in one in about 700 individuals, but most are wholly asymptomatic.
Most of them do not report problems more frequently than the general
population. There are a subset of individuals who have IgA deficiencies,
that do have problems. And finally there is a condition referred to as
transient hypogammaglobulinemia of infancy, which is recently frequent
and mimics the most closely common variable.

Problems with Normal Upper and Lower
Respiratory Tract Barriers to Infection

€ Unfavorable Anatomy
€ Abnormal mucus transport or rheology
• Cystic Fibrosis
• Secondary or Primary Ciliary Dysfunction
€ Allergy

Evaluation for Deficits in Respiratory Barri-
ers So the laboratory evaluation for primary humoral immunodeficiency should
include initially simply 5 hemiummuoglobulins in the blood, I, V, G, M & A.
One can also utilize information based on the majority of the individuals that
makes specific antibodies. There are two classes that you can easily get
€ History, Physical, Radiographic
information about. One is the natural antibodies that we make and set off
€ Screening Allergy Evaluation as red cells, which is called hemagglutination. These appear toward the

€ Sweat Test end of the first year of life and accumulate after that. The other is to
measure how many antibodies the patient has made to the routine travel
€ ENT Evaluation
immunization that he or she has perceived. Will give you some measure
€ Ciliary Evaluation - in most refractory cases after exclusion of more whether that individual can make antibodies. Remember if you are doing
common diagnoses these tests too early, like at six months of age, most of the antibodies can
be marked, but at a year later, most of these can be able to get some sense
at whether the child can make specific antibodies. This along with
immunoglobulins provides a good initial screening, and if they are normal
one will generally end up just waiting and evaluating further, only if
problems are more severe. And then those secondary evaluations would
include the following. Furthermore, looking at one individual to make
antibodies to saccharides will tell you something you can not get from
looking at antibodies response. There are individuals who have a particular
problem making antibodies with polysaccharides. The problem with that of
course, is that we normally do not expect children under two years of age
to make antibodies of polysaccharide to any great efficiency whatsoever. So
the test is fully useless under that age. And it is problematic to interpret off
before four or five years of age, because during that period of time, the
response is suboptimal, although it does occur. Also during IgG subclasses
may be inducing some patients.


€ Four major classes - IgM, IgG, IgA and IgE

€ Four subclasses of IgG - and two subclasses of IgA
€ Antibody bound to microbes can neutralize (virus), activate complement
and/or bind to specific receptors on phagocytes for IgG, IgA or IgE
€ Primary Ab response - Predominantly IgM
€ Secondary Ab - enhanced recall response, switch to IgG (IgA), largely
T cell dependent

Age-related Changes in Immunoglobulin So, the thing that is always important to know is that things change with

Concentrations age. You need to make sure that your laboratories report the values that
you’ve asked to, with a proper gauge related norm. Because if they are not,
they are often going to look low, when they are perfectly fine to the child.
The important thing to note then, is when your looking at IgG, there is a
Age IgG-mg/dl IgM-mg/dl IgA-mg/dl physiologic manner that occurs in about 4-6 months of age, that on
average, goes down to about 400 or so, and then rises thereafter. But it is
(% adult) (% adult) (% adult)
not definite that this child has an underlying immune deficiency. So you
Neonate 1031 (89) 11 (11) 2 (1) need to think of the values given in the context of age, and whether this
child was full term or not. Again norms for age are important.
4-6 months 427 (37) 43 (43) 28 (14)

7-12 months 661 (58) 54 (55) 37 (19)

25-36 months 892 (77) 61 (62) 71 (36)

6-8 years 923 (80) 65 (66) 124 (62)

Adult 1158 99 200

Secretory Immunity

€ Mucosal associated lymphoid tissues contain T and B lymphocytes

€ Secretory IgA - two IgA molecules linked to an epithelial derived
secretory component
€ IgA is absent from mucosal secretions at birth and reaches adult
concentrations at 6-8 years of age

When to Suspect Primary Ig or Antibody
Immunodeficiency So what are the diagnostic criteria by which we establish the diagnosis
from one another is immune deficiencies.

€ Ear and sinus infections more common than in the normal general
population; recurrent/refractory pneumonia or GI infections with viral
pathogens or Giardia are indicative of an antibody immunodeficiency.
€ Normal frequency

Age URTI Otitis Diarrhea

<1 year 6-7 1 (0-6) 1-2

1-2 years 8 1(0-6) 2

3-6 years 6-8 <1 (0-6) 2

Major Immunodeficiencies with a Primary
Deficit in Antibody Production

€ X-linked agammaglobulinemia and X-linked hyper-lgM syndrome -

onset of recurrent infections usually between 6-24 months of age
€ Common variable immunodeficiency - onset variable - may
present in adulthood
€ IgA deficiency - most common (1:700) often asymptomatic
€ Transient hypogammaglobulinemia of infancy

Laboratory Evaluation of Presumed Primary
Humoral Immunodeficiency

€ Initial - IgG, IgM and IgA, isoagglutinins and/or antibody to previous

vaccines -diphtheria, tetanus
€ Secondary evaluation if indicated
• Production of antibody in response to booster diptheria/tetanus and
pneumococcal vaccine (non-conjugated); assessment of
polysaccharide response unreliable at <2yr, difficult <5yr
• IgG subclasses
• Analysis of B cell number, T cell number end function in vitro

Diagnostic Criteria in Primary Humoral Im- X-linked agammaglobulinemia tells you right there that you should not
suspect any much in her.


€ X-linked agammaglobulinemia, markedly reduced

• All Ig classes, particularly IgG -Production of specific antibodies
• Numbers of B cells
• Normal number and function of T cells

Diagnostic Criteria in Primary Humoral Im-
munodeficiency You do see it in boys of course, and what one sees is fairly straightforward.
All immunoglobulin classes are markedly reduced, if not absent. IgG in
particular, being low, would never again in the first few months of life will
have an internal IG that may make it more difficult to interpret. They do not
€ X-linked hyperlgM syndrome
make specific antibodies, or make very little to immunize them. And this
• Clinical features similar to X-linked agammaglobulinemia plus disorder is characterized by the absence of new lymphocytes. T-cells are

increased risk for Pneumocystis, Cryptosporidium, neutropenia and completely normal. Now, the X-linked hyper IgM syndrome, these individu-
als present very much like X-linked agammaglobululinemia, but with some
additional features. So, they don’t make much IgG or any antibodies, but
• Markedly reduced IgG, IgA make plenty of IgM. The name hyper IgM syndrome refers to the fact, that
• High or Normal IgM the amount of IgM that they have is normal or is elevated by the appearance
of the G or A they have. They can not switch immunoglobulin plasma today,
• Normal numbers of B and T cells
every response they make looks like a primary. They make IgM, they make
• Defect in CD40 ligand expression IgM look like IgM. They do not do this, they do not get IgM, they do not have
€ Common variable immunodeficiency a recall. They have markedly reduced G and A, higher than normal IgM,

• IgG concentrations reduced by >50%, usually IgA and IgM also normal numbers of B and T-cells and they have a defect in the protein.

Common variable immune deficiencies. The most common finding here is
• Antibody responses to all classes of antigens diminished that the IgG concentration is reduced by more than 50%, commonly being
• B cells present, usually in normal numbers; T cell numbers and less in an adult in a 200-300 mm per liter that is more than the 50% below
the two standards used. IgA and IgM may also be reduced to that various
function variable
form. Their ability to make specific antibodies is apparent. The response
• Allergy, autoimmunity, malignancy may occur to all classes of antigens that are proteins and polysaccharides are
€ IgA Deficiency diminished. These cells are present and are usually there in normal
numbers, but not always. T-cell number and function varies. Some of these
• lgA <5 mg/dl
patients have T-cell function defects. In addition to the types of infections
• May occur in kindreds with common variable immunodeficiency or
that I have mentioned, they commonly engulf a lot of immune diseases, and
co-exist with IgG subclass deficiency; allergy/autoimmunity may co- malignancy may also develop. In fact, overall malignancy increases in

exist patients with immune deficiencies.

€ Deficiency of one or more of the IgG subclasses (IgG 1, 2, 3, 4)

IgA deficiency. By that I mean an IgA that is undetectable. There are a
• Significant if specific antibody production is low bunch of patients out there with IgA that are floating around, at about 50-
• IgG2, G4 - capsulated bacteria 75% of what is called a lower limit than normal. Those individuals identifies
another problem in antibody production, should not have difficulty with
• IgG3 - recurrent respiratory infections
infections. A true IG deficient person is less than five. It may occur in
• caveats - values should be markedly reduced; difficult <2-4 yr due hindrance, in association with common vertical and immunodeficiencies or
to low range of normals coexist with IgD subclasses. When it does, it is more likely to be associated

• may occur in association with IgA deficiency with a problem of recurring infection. Recall that I said that 1 in 700
individuals that is probably someone in this room that is IG deficient, and
yet, does not have any problems. It is significant if specific antibody
production is low. Remember, we have four IgD subclasses. The usual
definition of lower than normal is that they fall below the fifth percentile. By
definition if you do four tests, you have 4/5% of an opportunity to find an
abnormality. That is 20% of the time just by statistical normals, you do an
IgD set of subclasses, you are going to find one of them well. Don’t interpret
that as being abnormal. What one sees in individuals who have deficits in
G2 or G4, is definite cause of recurrent effects to the capsulated bacteria,
pneumococcus. Patients with IgG 3 deficiencies, commonly have a
recurrent respiratory infections, and lower respiratory tract infections. It is
very difficult when interpreting these under about 2-4 year of age, because
the value with set for IgD 1 are commonly so low, it is difficult to interpret.
Particularly IgD 4, even in an adult is the lower one than normal that
overlaps the level of delectability. So G4 deficiencies are almost undefin-
able. So these tests are worth doing only on a patient who you have not
found a deficit in total G and A, are were thinking of the context of looking

Transient Hypogammaglobulinemia of In- for specific antibody production.

fancy Finally transient hypogammaglobulinemia of infancy. What this appears to

represent is simply an attenuated or prolonged physiologic
hypogammaglobulinemia. You will recall the normal values fall in the
neighborhood of about four months of age, and if that is attenuated or
€ Accentuated and prolonged physiological hypogammaglobulinemia
prolonged, then there will be a deficit in IgG beyond the first six months out
(Ig(G predominantly) to 12-18-24 months of life. It is normal. But what you see in these

• Normal event in very low birth weight prematures individuals, is that IgG values increase with time. Specific antibody
responses are intact. That is if you are concerned and anxious, you can
• Ig increases with time, specific antibody responses are intact
look at whether the individual is making antibody immunizations that he or
(quantity may be slightly low), B cell and T cell numbers/function she has been given. The magnitude of that response may be somewhat
normal lower than in an otherwise normal child, but they do respond. B and T-cell
numbers in function are normal. This may be difficult to differentiate initially
• May be difficult to differentiate initially from CVID
from common variables. The common variables does not lock in percent
at a year of age. So if you see sort of a mixed picture with someone with a
low G, and relatively normal, slightly low A. A common variable is most
likely to be the case. You can evaluate the patient in one of two ways. You
can simply follow the patient, repeating the immunoglobulin values in a
matter of two months, depending on how the patient is doing, and how
anxious they are. Or you can look for production of specific antibodies as
I mentioned to see how well they are doing. Either study is reasonable, and
treatment of infections, treatment may begin.
So what about frequent humoral immune deficiency, I would think transient
hypergammaglobulinemia. Well the only real therapy that we have that is
specific is regular adhesions of intravenous immunoglobulin. That is
indicated in individuals with proved primary immune deficiency in which
they have no IgG, and/or deficits in specific antibody production, or maybe
indicated in secondary immunodeficiencies associated with diminished
specific antibody production. It is generally contraindicated in an isolated
IgA deficiency. The most common of course is allergies. Patients with
asthma commonly have the elevated IgGs. What I’m talking about are not
just to put modestly IgG’s’s. I’m talking about also very high IgGs. The most
common one that you heard about is called the hyper IgE syndrome. Those
individuals present as if they had a neutrophil or optimum defect, which I
will talk about next. And chronic or recurrent staphylococcal infections of
the skin and gram-negative staphylococcal and fungal infections of the
lungs, commonly engulfed in cavities in the lungs. They have a skin rash
that looks somewhat different than you have seen. The Wiskott-Aldrich
syndrome is another form of combined immune deficiency. It presents with
high values of IgG. The hallmark of this disorder is thrombocytopenia, and
it is the most penetrated form of leukemia. These patients presented with
thrombocytopenia uncover definite eczema and thrombocytopenia is
characteristic in that the platelets are small. It is about the only
thrombocytopenia where the platelets are small.

Treatment of Humoral Immunodeficiency
Unusual or unusually severe invasive infections with bacterial pathogens,
or opportunistic bacteria, organisms that would not ordinarily produce in
€ Regular Infusions of IGIV
healthy individuals. In those individuals you can expect to find a definite
• Proved primary immunodeficiency with low IgG and/or deficits in either in one of their barriers, and the common one being burns, or

specific antibody production deficiencies such as in diabetes. As you can probably guess, the outer
hand and both feet look like this as well. Anyone want to tell me what this
• Secondary immunodeficiency associated with diminished specific
is? So, the spleen is a good thing to have around. It is a filter. It is the most
anybody production - CLL, pediatric AIDS, bone marrow transplants efficient organ at removing non-antibody coated, complement opsonized
€ Contraindicated bacteria. So if you are a person who does not have preexisting immunity to
that bug, now all you got is complement and things like CRP, you want your
• Isolated IgA deficiency
spleen, because the spleen has a lot of macrophages in it, and that
organism is best at kicking out those cells that only have complement on
their to opsonize it. It is also a sight of antibody production. What about
opsonins? There are a whole bunch of copper proteins.
2). They move about three things: they converge at C3 in the middle, and
C3 does several things; if it is down to the surface of the particle it is
upside, when it is down, it is prereleasing a particle called C38 which is
chemotactic, which helps tract neutrophils, and it also then plays a role in
acting other common components forward down to the right and below,
which went down to the plasma membrane of certain organisms. So they
move from left to right beginning with C1, converging in C3, an alternative
pathway enters there as well. Again, converting on C3 is the key feature.
Now the only other thing to remember about this whole pathway, is with 2
laboratory tests, you can access the whole thing. You can screen your
patient with those 2 tests, and that is really all you need to know. So there
are two major types of problems the patients with complement dysfunction
present with is infections and one is not infections. The most common one
that you will see is a patient with recurrent invasive infections. About 5% of
the patients present with meningococcal infections for the first time,
actually have a copper disorder. The treatments will be greater than that if
the infection is unusual in type. So the frequency may go up to 10 or 15%
in those groups, whereas if you are looking at a young child with a B, it is
going to be less than 5%.

Syndromes Associated with Excess IgE

€ Modest elevations - atopy

€ Marked elevations - Generally >1000 IU
• Hyper Ig E syndrome - chronic/recurrent Staphylococcal >gram-
negative and fungal infections of skin, lungs
• Omenns syndrome, Wiskott Aldrich syndrome - forms of combined

Unusual or Unusually Severe Invasive Infec-
tions with Bacterial Pathogens or Opportu-
nistic Bacterial Fungi

€ Deficits in Cutaneous Barrier

• Burns
• Vascular insufficiency
€ Deficits in Systemic Innate Defenses
• Spleen
• Complement
• Phagocytes

Splenic Function

€ Filter - most efficient at removing non-antibody opsonized bacteria

€ A site of antibody production
€ Splenic absence/dysfunction predispose to overwhelming infection with
capsulated bacterial pathogens, particularly S pneumoniae


€ Proteins that when bound to the surface of cells enhance their ingestion
by phagocytes
€ Primitive opsonins - acute phase reactants
• Mannose binding protein (MBP)
• C-reactive protein (CRP); opsonin for pneumococci
• Others. e.g., fibronectin
€ Complement
€ Antibody


€ Complement activation is initiated through

• A cascade of proteins and regulated proteases
1. Classical pathway activated by IgG, IgM. CRP, MBP bound
to a microbe
2. Alternative pathway fluid phase activation amplified on microbe
• Activated complement -opsonic (C3b). chemotactic (CSa) and lytic
• Alternative >classical pathway activity diminished in neonates (50-
75% adult)

Complement Deficiency

€ Recurrent invasive infections with Neisseria meningitidis) or N gonorrhea

• 5% initial overall, greater with unusual type or older age, -30%
recurrent have defects
• Any component except C1, particularly C6-8 and in males,
• Recalcitrant skin, Recurrent invasive infections with pyogenic
bacteria; Staph, pneumococci; SLE
1. Defects in proximal complement components

Complement Deficiency Evaluation

€ Screening Tests
• CH - genetic deficiency except for C9 <10%, C9 -60%
• In males also do AH - alternative pathway - properdin
• Individual components to define specific defect

Complement Regulation

€ Membrane regulatory proteins inhibit activation of complement at the

surface of normal host cells - CR1, DAF, C8bp, CD59
€ Inhibitory serum components act to attenuate activation of complement
-Cl inhibitor - acting at C1; C4bp, Factors H and I - acting to block C3


€ Macrophages - resident phagocyte in most tissues; originate from

€ Neutrophils - critical line of defense against invading bacteria and fungi
€ Eosinophils are likely important in defense against metazoans

Neurophil Reserves

€ One-half of circulating neutrophils are marginated, can be rapidly

€ Bone marrow storage pool of mature neutrophils, bands and metas can
be rapidly released by cytokines and corticosteroids
• Release leads to "left shift"
• Immature forms are somewhat less functional
€ Neonate, especially the premature, have a limited storage pool

Neutrophil- Adherence and Chemiotaxis

€ Initial step in response to infection is adhesion to activated vascular

endothelium via B2 integrins, selectins
€ Chemotaxis - directed migration of leukocytes towards higher concentra-
tions of chemotactic factors
• Chemotactic factors include bacterial products and host derived
lipid (leukotrienes, PAF) and protein (chemokine) products

Neutrophil - Phagocytosis and Killing

€ Microbes are bound to neutrophils predominantly through receptor for

opsonins - collectins, IgG, C3b and C3bi
€ IgG Recep (FcR) and Compl. Recep engaged particles are efficiently
ingested and also trigger microbicidal mechanisms
• Respiratory burst -oxygen dependent
• Degranulation - myeloperoxidase; Defensins

Phagocyte Deficiency

€ Numeric
• Iatrogenic, autoimmune, genetic -G-CSFR mutation
€ Leukocyte adhesion deficiency
• Recurrent mucocutaneous and invasive tissue infections (non-
bacteremic) due to all bacterial pathogens; delayed cord separa-
• Type I - absence of CD18 B2 integrins) -Diagnosis - suspect -
persistent neutrophilia, confirm - flow cytometry for CD18, Mac-I,
• Type 2 - rare

Chronic Granulomatous Disease

€ Invasive infections due to catalase positive bacteria and fungi;

lymphadenopathy, hepatosplenomegaly, eczema and diarrhea
€ Age of onset typically first 6 months but may be much later
€ X-linked and autosomal dominant deficiency of phagocyte oxidase
€ Evaluation - NBT test for superoxide or FACS assay for H202
€ Therapy - prophylactic interferon ( and/or TMP/SMX, itraconazole

Severe/unusual Infections with
Intracellular/Cell-associated Microbes

€ T cell/Combined immunodeficiency
€ Infections with
• Viruses - particularly herpes group
• Intracellular bacteria, e.g., Mycobacteria, Listeria
• Protozoans- Pneumochysis, Toxoplasma, Cryptosporidium, Giardia
• Fungi -Cryptococcus, Histo, Cocci
• Mucocutaneous Candidiasis
€ Antibody production to newly encountered microbes also is compro-

T Cell Recognition and Effector Function

€ T cells recognize short peptides bound to self HLA molecules

€ CD4 (helper) T cells
• Recognize peptides bound to HLA-D molecules (class II MHC) on
specialized antigen presenting cells (e.g., macrophages, B cells)
€ CD8 (cytotoxic) T cells
• Recognize peptides bound to HLA-A, B, C (class I MHC) which are
found on nearly all cells

Mediators of CD4 (Helper) T Cell Function

€ Cytokines and cell surface ligands play a major role in helper function
€ B cell responses to protein antigens and the class of antibody produced
are dependent on T cell contact via CD40 ligand and cytokines, e.g., IL-4
= IgE, interferon-( = IgG
€ Loss of T cell help requite in combined cellular end humoral immunode-
ficiency, even if B cells are normal

Interleukins/lymphokines in Host Defense

€ TH1 lymphokines - IL-2, IFN~, end TNF - activate

macrophages/enhance defense vs intracellular pathogens
• Viruses, protozoa (Pneumocystis, Toxoplasma, Crypto), mycobac-
€ TH2 lymphokines - IL-4, IL-5, IL-'10 enhance IgE production, eosinophils
these mediate allergy and may protect against mucosal infection with

Macrophage Attraction and Activation by T

€ T cells and Macs secrete chemokines to attract each other to sites of

€ Macrophages are activated by cytokines secreted by T cells - interferon-
( GM-CSF and TNF, or by CD40 ligand
€ Activated macrophages have increased capacity to kill microbes -e.g.,
mycobacteria, Toxoplasma - via enhanced oxygen radical, nitric oxide
and other cidal substances

Severe Combined Immunodeficiency

€ Presentation usually <6-12 months of age

€ Opportunistic infections and recurrent pyogenic infections
€ Chronic diarrhea, FTT, eczema
€ Common forms
• X-inked
• ADA deficiency
• Autosomal recessive
• Variants

DiGeorge Syndrome

€ DiGeorge: Developmental Array Defect

• Cardiac/great vessel >parathyroid >substantive thymic defect
• Characteristic facies: mandibular hypoplasia, hypertelorism
• Microdeletion Chromosome 22


€ Ataxia-Telangiectasia: Mutation in protein required for DNA repair

• Ataxia, ocular telangiectasia
• Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4 and
T cell deficit
• Malignancy in patients and carriers

Initial Evaluation for Suspected
T Cell/combined Immunodeficiency

€ Lymphocyte Count
€ DTH skin testing - Candida, Mumps, Tet/Dip
• Unreliable in <1-2 years of age -placement and reading by trained
• HIV testing
• Chest radiograph - thymus

Assessment of CMI/T Cell Numbers and Func-
tion in Vitro

€ Indicated if DTH tests are negative and/or child <2 yr

€ Enumeration of T cell subsets, NK and B cells by flow cytometry using
2-color FACS and standard procedures - must use age related norms
€ General T cell function - proliferation to mitogens (e.g., PHA) and/or
antigens (e.g., candida, tetanus). This primarily measures a CD4

Normal Age-adjusted T Cell Subsets

1-6m 7-12m 13-24m 25-74m Adult

CD4 to- 3211 3128 2601 1668 1027


5-95% 1153- 739- 505- 505- 500-1800

5285 4463 2831 2831

CD4/CD 2.2 2.1 2.0 1.4 1.7


5-95% 0.9-3.5 0.8-3.4 0.6-3.4 0.7-2.1 0.4-3.0

Management of Combined Immunodeficiency

€ Bone-marrow transplant
€ Temporizing - IVIG, TMP-SMZ, aggressive treatment of infections,


€ Common things are common

€ Staged evaluation is indicated unless there is evidence of unusual or
invasive infections or FTT
€ Isolated deficits in antibody mediated immunity rarely present before 6-9

months of age

Mediators of Acute Inflammation

€ Recruitment of circulating neutrophils to sites of inflammation involves

sequential production of complement (C5a) and lipid mediators plat activ
factor, leukotriene;), followed by cytokines - IL-1, TNF and chemokines -
€ These induce adhesins (selectins, ICAMs) on vascular endothelium,
activate neutrophil ligands for these adhesins (e.g,. Integrins) and
stimulate chemotaxis

Pharmacologic Inhibitors of Inflammation

€ Cyclo-oxygenase inhibitors - e.g., NSAIDs, aspirin, indomethacin - act

by blocking the production of prostaglandins
• Indicated in the treatment of Kawasaki, ARF
• Theoretically could shunt precursors into the leukotriene pathway
€ Pentoxifylline - phosphodiesterase inhibitor
• May diminish the inflammatory response in part by inhibiting
production of TNF, IL-1
€ Thalidomide - reduces TNF production
-leprosy (ENL), wasting in Tb/HIV?

Pharmacologic Inhibitors of Inflammation

€ Corticosteroids are the most potent, broad

€ Inhibit production of lipid mediators (PAF, Leukotrienes) and pro-
inflammatory cytokines (TNF, I/-1, chemokines)
€ Inhibits CMI/T cell function, e.g., production of IL-2, IFN-(
€ Evidence favors use in early H influenzae meningitis, selected patients
with TB pericarditis or severe PCP, typhoid fever, airway obstruction in
croup& inf. mono

Antagonism of Pro-inflammatory Cytokines

€ IL-1 receptor antagonist, soluble IL-I and TNF receptors, IL-10,

monoclonal antibodies to IL-1, TNF
• Antagonize LPS/infection induced sepsis syndrome in animal
models disappointing in human trials to date
€ Antibodies to LPS disappointing to date in sepsis syndrome

Hematopoietic Growth Factors

€ G-CSF - useful in neutropenia of nearly all causes, including chemother-

apy induced congenital neutropenia, cyclic neutropenia, possibly
neonatal sepsis
€ GM-CSF -generally less useful due to potency, side effects, and broader