CONGENTIAL/PRIMARY IMMUNODEFICIENCIES

DISEASE GENE DEFECT MECHANISM PHENOTYPE NOTES

DEFECTS IN LYMPHOCYE MATURATION
Severe Combined Immunodeficiency (SCID)
X-LINKED SCID
Absent common cytokine receptor c
chain
IL-7 signals not received very few T-
cells begin maturation
-low T, low serum Ig, low NK
-normal or increased B (B cells dont
require IL-7 to proliferate)
Common chain essential part of
receptor complex for interleukins
-IL-7 reqd for T-cell maturation
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ADA Adenosine deanimase enzyme
(adenosine inosine)
Build up of toxic metabolites of purine
synthesis

-(mostly harms rapidly dividing cells)
-mostly blocks T-cell maturation
-humoral immunity reduced due to
absence T-cell help
-progressive loss of T, B & NK cells
-Can be treated with injections of absent
enzyme

-ADA (most common); PNP (2
nd
most)
PNP Purine nucleoside phosphorylase
(PNP gene; inosine hypoxanthine)
RAG1 &
RAG2
Unknown No VDJ recombination no functional
TCR or BCR
-complete absence no T or B cells
-incomplete absence range deficiency
Prior to bone marrow transplant, death
was 100%
IL-2 & IL-
7R, JAK3
Defective signal transduction
RETICULAR
DYSGENESIS
Mitochondrial gene ak2

-results in energy deficiencies
Level of myeloid-lymphoid stem cell -absence T & B lymphocytes
-absence most myeloid cells, incl.
granulocytes
-most severe form of SCID
-death within days of birth
B-cell only deficiencies
X-LINKED AGAMMA-
GLOBINEMIA
Brutons tyrosine kinase (Btk) Btk essential for signal transduction in
pre-B cells from pre-BCR

no signal no transduction, so cells die
after pre-B-cell stage
-absence gamma globulin (peak on
serum electrophoresis) in blood
-no peripheral B cells (B1 cells) in blood,
lymphoid tissues, no germinal centers or
plasma cells
-very low Ig levels, normal T & NK cells
-Btk on X-chromosome; most cases in
boys (but some auto recessive forms)
-in female carries, all mature B-cells have
same X-chromosome inactivated
-autoimmune disorders develop in 20%
Tx: pooled IVIg
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IgA

Varies, but IgA heavy chains (IgC)
normal
-block in differentiation of B-cells to IgA
secreting plasma cells
-low serum IgA w/ normal or elevated IgM
& IgG (clinically may be normal or have
increased susc. to diarrhea or resp infect)
-most common primary immunodeficiency
-usually, no therapy is needed
IgG3 Varies, but IgG heavy chains (IgC)
normal
-block in differentiation of B-cells to
IgG3 secreting plasma cells
-very low serum levels of specific IgG
isotype (clinically usually normal)
IgG3 is normally a potent activator of
complement some people have
increased risk of bacterial infx
T-cell only deficiencies
DIGEORGE
SYNDROME
(DGS)
Deletion at chromosome 22q11.2
(probably TBX1 gene encoding T-box 1
transcription factor)
- 3
rd
and 4
th
pharyngeal pouches do not
form absence or hypoplasia of thymus
& parathyroid glands
-T-cells absent of very low &
unresponsive to polyclonal activators
-Antibody levels normal
-increased susceptibility to Mycobacteria,
fungi & viruses (intracellular pathogens)
-improve by age 5 (residual or ectopid
thymic tissue elsewhere in body?)

-CATCH 22: cleft palate, facies, thymus,
cardiac defects, hypocalcemia
DEFECTS IN LYMPHOCYTE ACTIVATION & EFFECTOR FUNCTIONS
X-LINKED HYPER IgM
SYNDROME
-CD40L defect -lack of CD40L on T helper cells
defective T-cell help for B-cell &
macrophage activation
-normal B & T-cell #s but no isotype
switching (so, IgM = major serum Ab)
-severe deficiency of CMI against
intracellular microbes
-defect in CMI very high susceptibility
to fungus Pneumocystis jiroveci
-rare: autosomal recessive forms (defects
in CD40 or AID)
HYPER IgE (Job)
SYNDROME
STAT3 mutations -abnormally high IgE serum levels
high eosinophils
-chronic skin infections (& mucosal infx)

-often fatal b/c succumb to secondary
infections; painful

COMMON VARIABLE
IMMUNODEFICIENCY
Defects in effector mechanisms different mechanisms:
B-cell: no isotype switching, not activated
T-cell: not activated, no cytokine secreted
excessive Tregs
-mature B cells but NO plasma cells
-reduced serum levels Ig, impaired Ab
response, pyogenic bacterial
infections, autoimmune d/o, malignancy
-can be diagnosed early in childhood or
later in life
-sporadic and familial cases
-familial cases both auto dom & recessive
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CLASS I

TAP1, TAP2 Decreased MHC I expression on all cells

-defective CD8+ T-cell activation
-increased susc. to respiratory
BACTERIAL infections (not viruses =
weird)
-S. pneumonia most common bacterial
infection worry about
CLASS II Transcription factors regulating MHC II
expression
Low or absent MHC II expression on
macrophage, dendritic cell & B-cells
-defective CD4+ T-cell activation, CMI,
& humoral responses to proteins
-cannot make DTH response or produce
protective Ab to protein Ag fatal
DEFECTS IN TCR
EXPRESSION/
SIGNALING
CD3 subunits, ZAP70 Defective TCR-mediated signaling
decr. IL-2, IL-2R & IFN- production
-normal or elevated numbers of blood
lymphocytes

chronic mucocutaneous candidiasis:
defective T-cell cytokine production
susc. to Candida sp.
DISEASE GENE DEFECT MECHANISM PHENOTYPE NOTES
DEFECTS IN INNATE IMMUNITY
Complement
C6-C9 Loss of formation of MAC -decreased C6-C9 levels -increased susc. to Nisseria infections
Professional Phagocytes
CHRONIC
GRANULOMATOUS
DISEASE (CGD)
-NADPH oxidase, needed for generation
of superoxide ions & hydrogen peroxide
-most common form is X-linked (91kDa)
but can be auto recessive (22kDA)
-phagocytes cannot kill ingested
bacteria or fungi (esp. catalase positive
organisms)
-persistent microbial Ag induce persistent
T-cell helper response granulomas
-frequent pneumonia; abscesses in skin,
liver, viscera; infections in lymph nodes
(lymphadenitis)
- lab test: nitroblue tetrazolium (NBT) -
NBT turns yellow blue when it
combines w/ released H+, so if no H+,
(meaning no NADPH oxidase) it wont
turn blue
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LAD 1


2 chain of 2 integrins (CD18) -defective 2 integrin expression
decreased leukocyte adhesion during
infection
-leukocytosis w/ defective recruitment
of lymphocytes to areas of infection
-recurrent bacterial & fungal infections
-severe growth & mental retardation
-neutrophilia but no PNMs in pus

-also: delayed separation of umbilical
cord & early loss of teeth (periodontal
disease)
LAD 2 GDP fucose transporter -defective synthesis of sialyl-Lewis
component of E- & P-selectins
CHEDIAK-HIGASHI
SYNDROME
LYST gene (lysosomal trafficking
regulator)
-defective lysosomal granule exocytosis -defective phagolysosome fusion and
function in neutrophils, macrophages,
dendritic cells, NK cells, CTLs, etc.
-recurrent infections by pyogenic bacteria
-assoc w/ albinism & neuropathies
-giant cell lysosomes in PNMs
NK cell deficiencies
TOLL LIKE
RECEPTOR DEFECTS
Only known = toll & interleukin-1
receptor-associated kinase-4
Type I IFN signaling defects specific
viral susceptibilities
-increased susceptibility to severe
herpes infections
-NK cells are also low to absent in all
forms SCID

Diagnosis of Primary Immunodeficiencies:
B-cell defects: reduced serum Ig, reduced responses to vaccines, reduced B-cell counts, absent or small follicles in lymphoid tissue
T-cell defects: reduced T-cell counts, reduced responses to polyclonal T-cell activators, deficient delayed-type hypersensitivity (DTH) reactions



AQUIRED/SECONDARY IMMUNODEFICIENCIES
AGE -newborn to age 2: unable to produce effective humoral response to T-independent Ag (e.g., polysaccharides); most susceptible to herpesvirus infections
-elderly (>70 yoa): thymic atrophy reduced T-cell responses, reduced response to vaccines, increased autoimmunity
MALNUTRITION -marasmus/cachexia: chronic starvation, does NOT itself cause immunodeficiency
-Kwashiorkor: causes immunodeficiency; occurs with life threatening illnesses (trauma, sepsis); no adaptation of metabolism is possible due to acute stress;
body mass preserved; CMI depressed, severe lymphopenia, & loss of DTH
RADIATION &/OR CANCER CHEMO Reduced stem cell populations (collateral damage)
CANCERS OF LYMPHOID SYSTEM Reduced environment for lymphocyte precursor development
TX W/ IMMUNOSUPRESSIVE DRUGS T-cell deficiency most common result (includes transplant recipients, autoimmune dz patients including anti-cytokine Ab therapy, cancer chemo)
INFECTION OF CELLS IMMUNE
SYSTEM
-AIDS: depletes CD4+ T-cells
-Measles virus: suppresses T-cell proliferation & responsiveness via soluble virokine
-CMV: infects myeloid precursors & encodes IL-10 mimic (IL-10 = immunosuppressive cytokine)
SPLENECTOMY Reduced ability to clear encapsulated micro-organisms (Pneumococcus)
-individuals w/ sickle cell anemia = functionally asplenic due to recurrent infarcts
-surgical splenectomy occurring after trauma to spleen & other conditions