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IMMUNOLOGY

Primary Immunodeficiency Disorders

A 6-month-old boy with recurrent bacterial infections and absent tonsils. You think it's SCID. It's not. Here's why that mistake costs you a board question.

Quick — commit before you learn

A 6-month-old boy presents with recurrent sinopulmonary infections starting at 5 months of age. Physical exam shows absent tonsils and no palpable lymph nodes. Labs show undetectable IgG, IgA, IgM. Flow cytometry shows normal T cell numbers.

What's the diagnosis?

PROGRESS
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The Big Branch: What Part of the Immune System Is Broken?
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Every immunodeficiency question on boards comes down to ONE decision first: which arm of the immune system failed?

Think of it like a shield with four layers. Each layer breaks differently:

BranchWhat's BrokenInfection PatternTiming
B Cell (Humoral) Antibody production Encapsulated bacteria (Strep pneumo, H. flu, Pseudomonas), enteroviruses, Giardia After 6 months (maternal IgG wanes)
T Cell (Cellular) Cell-mediated immunity Intracellular organisms: viruses (CMV, EBV), fungi (Candida, PJP), mycobacteria Early (months)
Combined (B + T) Both arms Everything — all of the above, often severe/fatal Very early (weeks-months)
Phagocyte Neutrophil/macrophage function Catalase-positive organisms (Staph, Aspergillus, Serratia, Nocardia, Burkholderia) Variable
Complement Complement cascade Neisseria (late complement) or encapsulated bacteria (early complement) Variable
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Memory hook: How to remember which infections go with which deficiency...
"B cells fight Bacteria that are encapsulated. T cells fight Things that hide inside cells. Phagocytes eat what's catalase-positive (because those bugs neutralize the phagocyte's own H2O2 weapon). Complement kills Neisseria — Close the Net."

Why 6 months matters for B cell deficiencies: Maternal IgG crosses the placenta and protects the baby. It has a half-life of ~21 days and is mostly gone by 6 months. That's when B cell deficiencies unmask — the baby's own immune system has to take over, and it can't.

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The Big 10: Disease Cards (tap to flip)
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Boards tests ~10 immunodeficiencies heavily. Each one has a board buzzword that gives it away instantly. Learn the buzzword first, then the mechanism.

B CELL
Bruton's (X-linked) Agammaglobulinemia
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Defect: BTK gene mutationBruton Tyrosine Kinase — a signaling enzyme needed for pre-B cell maturation in bone marrow. Without it, B cells never leave the assembly line. → no mature B cells
Buzzword: absent tonsils/lymph nodes, boy <1 year
Labs: All Ig classes absent. No B cells on flow. T cells normal.
Infections: Encapsulated bacteria, enteroviruses
Treatment: IVIG for life
X-linked → boys only. Starts ~6 months when mom's IgG runs out.
B CELL
Common Variable Immunodeficiency (CVID)
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Defect: B cells present but can't differentiate into plasma cells → low antibodies
Buzzword: Young adult with recurrent sinopulmonary infections + autoimmune disease
Labs: Low IgG (+ often IgA, IgM). B cells present but dysfunctional.
Infections: Same bugs as Bruton's + higher risk of lymphoma and autoimmune disease
Treatment: IVIG
Most common SYMPTOMATIC primary immunodeficiency. Think "Bruton's but later and with B cells still there."
B CELL
Selective IgA Deficiency
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Defect: Low/absent IgA, other Ig normal
Buzzword: Anaphylaxis after blood transfusion in someone with recurrent mucosal infections
Labs: IgA <7 mg/dL. IgG and IgM normal.
Infections: Mucosal (sinopulmonary, GI — Giardia). Many are asymptomatic!
Treatment: Avoid blood products with IgA (can make anti-IgA antibodies)
Most common overall primary immunodeficiency (1 in 500). Can progress to CVID. The transfusion reaction is THE board question.
T CELL
DiGeorge Syndrome (22q11.2 deletion)
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Defect: 3rd/4th pharyngeal pouchThe 3rd pouch makes the inferior parathyroids + thymus. The 4th pouch makes the superior parathyroids. Both are deleted. No thymus = no T cell maturation. No parathyroids = no PTH = hypocalcemia. fails to develop → no thymus
Buzzword: CATCH-22 — Cardiac defects, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia/Hypoparathyroidism. Chromosome 22.
Labs: Low T cells. Low PTH. Low calcium. B cells present but dysfunctional (no T cell help).
Infections: Viral, fungal (Candida), PJP
Treatment: Thymus transplant (severe). Calcium supplementation.
Boards loves the tetany/seizure from hypocalcemia presentation. If a baby has heart defect + low calcium + infections = DiGeorge.
COMBINED
SCID (Severe Combined Immunodeficiency)
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Defect: Multiple possible — most common is IL-2R gamma chain (X-linked)The gamma chain is shared by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. Knocking it out cripples ALL lymphocyte signaling. That's why it's "combined" — T cells AND B cells fail. or adenosine deaminase (ADA) deficiencyADA breaks down adenosine and deoxyadenosine. Without it, dATP accumulates in lymphocytes and is directly toxic — it kills the cells that are supposed to protect you.
Buzzword: Absent thymic shadow on CXR + failure to thrive + severe infections in first weeks of life
Labs: Low T cells (always). B cells absent or present-but-nonfunctional. Low Ig.
Infections: EVERYTHING — bacteria, viruses, fungi, opportunistic. Fatal without treatment.
Treatment: Bone marrow transplant. Gene therapy (for ADA-SCID).
"Bubble boy" disease. NEVER give live vaccines. Fatal by age 2 without transplant.
COMBINED
Hyper-IgM Syndrome
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Defect: CD40L (CD154) mutationCD40L on T helper cells binds CD40 on B cells. This interaction triggers class switching — the process where B cells switch from making IgM to IgG, IgA, or IgE. Without it, B cells are stuck making only IgM forever. → B cells can't class switch
Buzzword: Elevated IgM + low IgG, IgA, IgE
Labs: Very high IgM. Very low everything else.
Infections: Same as B cell + Pneumocystis (PJP) and Cryptosporidium
Treatment: IVIG + TMP-SMX prophylaxis
Classified as combined because CD40L is on T cells (it's a T cell signaling defect that screws B cells). The Cryptosporidium → sclerosing cholangitis combo is a board classic.
COMBINED
Wiskott-Aldrich Syndrome
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Defect: WASP gene mutationWASP (Wiskott-Aldrich Syndrome Protein) organizes the actin cytoskeleton. Without it, platelets are small and dysfunctional, T cells can't form proper immunological synapses, and the whole immune response falls apart. → actin cytoskeleton dysfunction
Buzzword: The triad — Thrombocytopenia (small platelets) + Eczema + recurrent Infections
Labs: Low/small platelets (MPV low). Low IgM. Elevated IgA and IgE.
Infections: Encapsulated bacteria, viruses. High risk of lymphoma and autoimmune disease.
Treatment: Bone marrow transplant
X-linked. Mnemonic: WATER — Wiskott-Aldrich = Thrombocytopenia, Eczema, Recurrent infections. The SMALL platelets are the giveaway — every other cause of low platelets has normal or large ones.
PHAGOCYTE
Chronic Granulomatous Disease (CGD)
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Defect: NADPH oxidase deficiencyPhagocytes kill bacteria with a "respiratory burst" — NADPH oxidase generates superoxide (O2-) which becomes H2O2, bleach (HOCl), and other reactive oxygen species. Without it, the phagocyte can eat the bacteria but can't kill it. The bacteria just... sits there. Inside the cell. → no respiratory burst
Buzzword: Negative nitroblue tetrazolium (NBT) test / abnormal dihydrorhodamine (DHR) flow cytometry
Labs: NBT stays clear (no blue). DHR doesn't fluoresce.
Infections: Catalase-positive organisms ONLY: S. aureus, Aspergillus, Serratia, Nocardia, Burkholderia cepacia
Treatment: IFN-gamma prophylaxis + TMP-SMX + itraconazole
Why catalase-positive? Normal bacteria make H2O2 as a waste product — phagocytes steal it to kill them. Catalase-positive bugs destroy their own H2O2, so the phagocyte has NO killing mechanism at all.
PHAGOCYTE
Chediak-Higashi Syndrome
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Defect: LYST gene mutationLYST controls lysosomal trafficking. Without it, lysosomes can't fuse properly — they merge together into giant, dysfunctional granules. This affects neutrophils (can't degranulate to kill), melanocytes (pigment clumps instead of spreading), and platelets (bleeding issues). → defective lysosomal trafficking
Buzzword: Giant granules in neutrophils + partial oculocutaneous albinism + peripheral neuropathy
Labs: Peripheral smear shows giant cytoplasmic granules in WBCs
Infections: Pyogenic bacteria (Staph, Strep)
Treatment: Bone marrow transplant
Autosomal recessive. The "pale kid with giant granules" = Chediak-Higashi on every board exam. Can progress to "accelerated phase" (HLH-like syndrome) which is fatal.
COMPLEMENT
Complement Deficiencies
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C1-C4 (early): SLE-like syndrome + recurrent encapsulated bacteria (immune complexes aren't cleared)
C3: Severe — recurrent pyogenic infections (C3 is the hub of all 3 pathways)
C5-C9 (late/MAC): Recurrent Neisseria infections (meningococcus, gonococcus)
C1 esterase inhibitor: Hereditary angioedema (NOT urticaria — no mast cells involved)
Test: CH50 screens total complement function. 0 = complete deficiency somewhere.
Board formula: "Young adult with recurrent meningococcal meningitis" = late complement deficiency. "Recurrent angioedema without urticaria" = C1-INH deficiency.
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Sort It: Drag Findings to the Right Deficiency
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Drag each finding to the immune branch it belongs to. This is exactly how boards frames it — they give you the finding and expect you to know which system is broken.

B Cell (Humoral)

T Cell (Cellular)

Combined

Phagocyte

Complement

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Decision Tree: "This Kid Has Recurrent Infections"
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Boards gives you a kid with infections. You need to work through the labs to find the deficiency. This is the algorithm.

Step 1: What TYPE of infections?
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Elimination Game: 6 Clinical Scenarios
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Board-style vignettes. Four options, one correct. The explanation matters more than the answer.

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Quiz: 12 Board-Style Questions (randomized)
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Every reload picks 6 from a pool of 14 and shuffles the answer order. No memorizing the pattern.