3.6 about 24 minDeep Learning viewL3 p.44–46L2 p.14, 19, 21–22

Primary immunodeficiencies

Each inherited immunodeficiency removes one part of the system, and the infections that follow are the ones that part normally controls. Read every case as defect → infection pattern → lab clue.

Reading a defect from its infections

L3 p.44–46

The microbe tells you what is missing. Antibody and complement deal with bacteria that live outside cells, especially encapsulated bacteria that must be opsonized before phagocytes can eat them. T cells deal with organisms that live inside cells (viruses, mycobacteria, fungi, Pneumocystis). Neutrophils deal with bacteria and molds at the tissue surface.

Teaching schematic

B-cell line: antibody (encapsulated bacteria, enteroviruses, Giardia; after 6 months)

Stem cell✕ SCIDγc, ADA, RAG; ↓ TRECsPre-B cell✕ BrutonBTK; no B cellsMature B (IgM)✕ Hyper-IgMCD40L; IgM onlyClass switch✕ CVID / IgA def.no plasma cells; IgA ↓Plasma cell

T-cell line: viruses, fungi, Pneumocystis, mycobacteria; early infancy

Stem cell✕ DiGeorge22q11; no thymus, ↓ Ca²⁺Thymus → T cell✕ IL-12R def.no Th1; mycobacteria✕ JobSTAT3; no Th17; ↑ IgE✕ CMCAIRE; Candida

Whole-system defects

✕ Ataxia–telangiectasiaATM; ↑ AFP; IgA ↓✕ Wiskott–AldrichWAS; small platelets, eczema✕ Phagocytes (Ch. 2)LAD, CGD, Chédiak–Higashi✕ Complement (3.7)C5–C9 → Neisseria
Where each defect sits on the path from stem cell to effector, with its infection pattern and laboratory clue.

Infection pattern points to the missing armL3 p.44–46, 54

  • Antibody (B cells)

    Typical infections
    Recurrent sinusitis, otitis, pneumonia with S. pneumoniae, H. influenzae; enteroviruses; Giardia
    Timing and other clues
    Starts after about 6 months, when maternal IgG wanes

  • T cells

    Typical infections
    Viruses, Candida, Pneumocystis, mycobacteria, intracellular bacteria
    Timing and other clues
    Early in infancy; failure to thrive; also antibody problems because B cells need help

  • T and B cells (combined)

    Typical infections
    All of the above, often with chronic diarrhea and thrush
    Timing and other clues
    First weeks of life; live vaccines are dangerous

  • Phagocytes

    Typical infections
    S. aureus, catalase-positive bacteria, Aspergillus; skin and gum infections
    Timing and other clues
    Pus absent (adhesion defect) or granulomas (killing defect)

  • Terminal complement

    Typical infections
    Recurrent Neisseria
    Timing and other clues
    Often first episode in adolescence (3.7)

B-cell defects: Bruton, selective IgA, CVID

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  • X-linked (Bruton) agammaglobulinemia. BTK encodes a tyrosine kinase that pre-B cells need to signal through their early receptor. Without it, B cells stop at the pre-B stage: no B cells in the blood, all immunoglobulin classes very low, and tonsils and lymph nodes are tiny because they lack follicles and germinal centers. Boys are well until about 6 months, when maternal IgG runs out, then have recurrent bacterial infections and dangerous enteroviral infections (including vaccine polio). T-cell immunity is normal. Live vaccines are contraindicated; treatment is lifelong immunoglobulin.
  • Selective IgA deficiency. The most common primary immunodeficiency; the cause is unknown. Most patients are asymptomatic. Some have airway and gastrointestinal infections (Giardia), autoimmune disease or atopy. Serum IgA is very low with normal IgG and IgM. Two practical traps: patients may have anaphylaxis to IgA in blood products, because they make antibodies against IgA (give washed red cells or blood from IgA-deficient donors), and IgA-based celiac serology is falsely negative.
  • Common variable immunodeficiency (CVID). B cells are present but fail to differentiate into plasma cells; IgG and IgA (often IgM) are low and vaccine responses poor. Diagnosis is usually after puberty. Recurrent sinopulmonary infections lead to bronchiectasis; patients also have autoimmune disease and a higher risk of lymphoma.
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Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

X-linked agammaglobulinemia (Bruton)

Bruton: no B cells, all classes lownormalB cellsIgMIgGIgAIgE
Serum immunoglobulins and B cells (schematic).
  • IgG, IgA, IgE very low
  • No B cells; IgM also absent: B cells never mature (BTK)
  • Encapsulated bacteria and enteroviruses after 6 months
  • Tiny tonsils and nodes

Step 1 · What they share

What do the two boys share?

Select every feature that both show.

T-cell defects: DiGeorge, IL-12 receptor, Job, mucocutaneous candidiasis

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  • DiGeorge syndrome (thymic aplasia). A 22q11.2 microdeletion disturbs development of the 3rd and 4th pharyngeal pouches, which form the thymus and parathyroids, and of the cardiac outflow tract. CATCH-22: Cardiac conotruncal defects (tetralogy of Fallot, truncus arteriosus), Abnormal facies, Thymic hypoplasia (T-cell deficiency: viral and fungal infections), Cleft palate, Hypocalcemia from absent parathyroids (tetany in the newborn). Labs: low T cells, low PTH and calcium, no thymic shadow on chest x-ray. Blood products must be irradiated to prevent transfusion GVHD. The genetics continue in Chapter 5: chromosomal syndromes.
  • IL-12 receptor deficiency (autosomal recessive). Th1 cells cannot develop, so IFN-γ is low and macrophages are never activated. Result: disseminated mycobacterial and fungal infections, sometimes after BCG vaccination: the most common cause of Mendelian susceptibility to mycobacterial disease.
  • Autosomal dominant hyper-IgE (Job) syndrome. A STAT3 mutation prevents Th17 cells from forming, so neutrophils are not recruited to infected tissue. FATED: coarse Facies, cold (noninflamed) staphylococcal Abscesses, retained primary Teeth, very high IgE with eosinophilia, Dermatologic problems (eczema); plus fractures from minor trauma.
  • Chronic mucocutaneous candidiasis. T cells fail against Candida: persistent, noninvasive Candida infection of skin, nails and mucous membranes. The classic form is caused by AIRE defects (APS-1, 3.5). Lab clue: no in-vitro T-cell proliferation and no skin reaction to Candida antigen.
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Combined and syndromic defects: SCID, ataxia–telangiectasia, hyper-IgM, Wiskott–Aldrich

L3 p.46
  • Severe combined immunodeficiency (SCID). Several defects with one result, no functional T cells and therefore no useful antibody: IL-2 receptor common γ chain (X-linked, most common; the chain is shared by the IL-2, -4, -7, -9, -15 and -21 receptors, so T and NK cells fail to develop); adenosine deaminase deficiency (autosomal recessive; toxic deoxyadenosine metabolites kill lymphocytes); RAG mutations (no V(D)J recombination, 3.1). Infants have failure to thrive, chronic diarrhea, thrush and recurrent viral, bacterial, fungal and protozoal infections. Labs: low TRECs (T-cell receptor excision circles, DNA loops cut out during TCR rearrangement in the thymus; their absence on a newborn blood spot is the basis of newborn screening), no thymic shadow, no germinal centers, low T cells. Avoid live vaccines; give irradiated blood; treat with stem-cell transplantation.
  • Ataxia–telangiectasia. ATM encodes a kinase that senses DNA double-strand breaks and halts the cell cycle (through p53) for repair. Without it, mutations accumulate and lymphocyte gene rearrangements fail. Triad: cerebellar ataxia in early childhood, oculocutaneous telangiectasias, and IgA (also IgG, IgE) deficiency with sinopulmonary infections. Raised AFP is the consistent lab clue. Patients are very sensitive to radiation (limit x-rays) and have a high risk of lymphoma and leukemia: the link to DNA-repair genes in Chapter 7.
  • Hyper-IgM syndrome. Usually CD40 ligand deficiency on helper T cells (X-linked). B cells cannot switch classes or form germinal centers: IgM normal or high, IgG, IgA and IgE very low. Because CD40L also activates macrophages, boys get opportunistic infections (Pneumocystis, Cryptosporidium, CMV) as well as severe pyogenic infections early in life.
  • Wiskott–Aldrich syndrome. The WAS gene (X-linked) organizes the actin cytoskeleton of blood cells, so leukocytes and platelets function and move poorly and antigen presentation is defective. WATER: Wiskott–Aldrich, Thrombocytopenia with characteristically small platelets (petechiae, bleeding), Eczema, Recurrent pyogenic infections. IgM low to normal (poor responses to polysaccharide antigens), IgA and IgE raised. Higher risk of autoimmune disease and lymphoma.
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Bridge: phagocyte defects (LAD, CGD, Chédiak–Higashi)

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The lecture's immunodeficiency tables cover lymphocytes. Phagocyte defects were taught with inflammation; they complete the picture because each removes one step of neutrophil function, and the step tells you the infection and the test.

  • Leukocyte adhesion deficiency type 1

    Step that fails
    Adhesion: no β2-integrin (CD18), so neutrophils cannot stick to endothelium and leave the vessel
    Clinical clue
    Delayed umbilical cord separation, skin and gum infections without pus, poor wound healing
    Lab clue
    Very high blood neutrophil count; absent CD18 by flow cytometry

  • Chronic granulomatous disease

    Step that fails
    Killing: no NADPH oxidase, so no oxidative burst
    Clinical clue
    Infections with catalase-positive organisms (S. aureus, Serratia, Nocardia, Aspergillus); granulomas
    Lab clue
    Abnormal nitroblue tetrazolium or dihydrorhodamine test

  • Chédiak–Higashi syndrome

    Step that fails
    Phagolysosome fusion: lysosomal trafficking defect
    Clinical clue
    Recurrent pyogenic infections, partial albinism, neuropathy, bleeding
    Lab clue
    Giant granules in neutrophils

Knowledge check · 3.6

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 6 correct
  1. Q1Bruton agammaglobulinemiaL3 p.44

    A 9-month-old boy has had three episodes of otitis media and one of pneumococcal pneumonia since age 6 months. His tonsils are barely visible. Flow cytometry shows no CD19⁺ cells; T-cell numbers are normal. IgG, IgA and IgM are all very low.

    Which defect explains his disease?

  2. Q2Selective IgA deficiencyL3 p.44

    A 26-year-old woman with recurrent sinusitis and two episodes of giardiasis is being evaluated for celiac disease; her IgA anti–tissue transglutaminase is negative despite a biopsy showing villous atrophy. Serum IgA is undetectable; IgG and IgM are normal.

    Which precaution matters most if she ever needs a transfusion, and why?

  3. Q3DiGeorge syndromeL3 p.45

    A 2-day-old boy has jerking movements and carpopedal spasm. He has a cleft palate and an echocardiogram shows truncus arteriosus. Serum calcium is 6.2 mg/dL and PTH is low; the chest x-ray shows no thymic shadow.

    Which finding is also expected?

  4. Q4Hyper-IgM (CD40L)L3 p.11, 46

    A 14-month-old boy has Pneumocystis pneumonia after several bacterial ear and lung infections. IgM is raised; IgG, IgA and IgE are almost undetectable. B cells are present in normal numbers, but a lymph node biopsy shows no germinal centers.

    Which molecule is most likely defective?

  5. Q5SCID (ADA) and TRECsL3 p.46

    A newborn's routine dried-blood-spot screen shows undetectable T-cell receptor excision circles (TRECs). At 3 months he has thrush, chronic diarrhea and poor weight gain. Both T and B cells are very low, NK cells are low, and his red-cell adenosine deaminase activity is absent.

    Why are his lymphocytes missing?

  6. Q6Job syndrome (STAT3, Th17)L3 p.45

    A 12-year-old boy has had recurrent skin abscesses with Staphylococcus aureus that are strangely painless and not red, two pneumonias, eczema since infancy and a forearm fracture after a minor fall. Several primary teeth have not fallen out. IgE is 8,000 IU/mL with eosinophilia.

    Which pathway is defective?

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