4.2 Immune Dysregulation and Lymphoid Disease
Key Takeaways
- Map recurrent infections to the missing defense: neutrophils for pyogenic organisms, antibodies for encapsulated bacteria, T cells for viral and fungal control, complement for opsonization and Neisseria.
- Hypersensitivity questions are mechanism and timing questions: IgE mast cells, IgG or IgM cell targeting, immune complexes, or delayed T-cell inflammation.
- Primary immunodeficiency vignettes use age of onset, infection type, lymphoid tissue, platelet size, calcium level, and special stains or oxidative burst tests as discriminators.
- Autoimmune disease clues often combine antibody specificity with tissue pattern, such as anti-dsDNA nephritis, anti-CCP rheumatoid arthritis, linear Goodpasture staining, or receptor stimulation in Graves disease.
- Leukemia and lymphoma questions are solved by cell lineage, age, smear or biopsy morphology, CD markers, translocations, and whether disease spreads contiguously or extranodally.
- Immunosuppressive and biologic drugs are tested through the immune pathway they block and the infection, malignancy, or autoimmune adverse effect that follows.
Start With the Immune Job That Failed
Immune vignettes are easiest when the infection pattern is translated into the missing host defense. Neutrophils handle acute pyogenic bacteria and fungi; neutropenia or defective adhesion produces recurrent bacterial infections with poor pus formation. B cells and antibodies protect mucosal and respiratory surfaces against encapsulated organisms. T cells control viruses, fungi, and intracellular pathogens and provide help for antibody class switching. Complement opsonizes bacteria through C3b, forms membrane attack complex through C5-C9, and drives inflammation through C3a and C5a.
Splenic macrophages clear opsonized encapsulated organisms from blood.
| Recurrent clue | Missing defense | Classic examples |
|---|---|---|
| Sinopulmonary pyogenic infections after 6 months | Antibody production | Bruton agammaglobulinemia, common variable immunodeficiency |
| Viral, fungal, and opportunistic infections | T-cell immunity | Severe combined immunodeficiency, DiGeorge syndrome, advanced HIV |
| Catalase-positive abscesses | Oxidative burst | Chronic granulomatous disease |
| Delayed cord separation and no pus | Neutrophil adhesion | Leukocyte adhesion deficiency |
| Neisseria infections | Terminal complement | C5-C9 deficiency or eculizumab effect |
| Severe recurrent pyogenic infections | C3 opsonization | C3 deficiency |
Adaptive immunity is tested through antigen presentation and cytokine logic. Major histocompatibility complex class I presents endogenous antigens to CD8+ cytotoxic T cells, which kill virally infected or malignant cells. Major histocompatibility complex class II presents exogenous antigens to CD4+ helper T cells. T helper 1 cells activate macrophages through interferon-gamma and are central to granuloma formation. T helper 2 cells promote IgE, eosinophils, and allergic or helminth responses.
T helper 17 cells recruit neutrophils and protect mucocutaneous barriers; defects predispose to Candida and Staphylococcus infections. Regulatory T cells limit autoimmunity through tolerance mechanisms.
Immunodeficiency Pattern Recognition
Severe combined immunodeficiency causes early, severe bacterial, viral, fungal, and protozoal infections; the X-linked form involves the common gamma chain used by several interleukin receptors. Adenosine deaminase deficiency is an autosomal recessive form with toxic purine metabolites injuring lymphocytes. DiGeorge syndrome is thymic aplasia from failed third and fourth pharyngeal pouch development, causing T-cell deficiency, hypocalcemia, cardiac defects, and absent thymic shadow.
Bruton agammaglobulinemia appears after maternal IgG wanes: boys develop recurrent sinopulmonary infections, absent tonsils, and very low immunoglobulins because B-cell maturation fails. Common variable immunodeficiency appears later with low plasma cells, recurrent respiratory infections, autoimmune disease, and lymphoma risk. Hyper-IgM syndrome is defective CD40 ligand signaling, so B cells cannot class switch; IgM is high or normal while IgG, IgA, and IgE are low. Wiskott-Aldrich syndrome combines eczema, recurrent infections, and thrombocytopenia with small platelets.
Selective IgA deficiency can be silent, but it is associated with mucosal infections, celiac disease, and anaphylaxis to plasma products.
Phagocyte disorders have different clues. Chronic granulomatous disease has impaired nicotinamide adenine dinucleotide phosphate oxidase, so the respiratory burst fails; catalase-positive organisms survive because they degrade their own hydrogen peroxide. Leukocyte adhesion deficiency has defective CD18 integrins, delayed umbilical cord separation, marked neutrophilia, and absent pus. Chediak-Higashi syndrome has defective lysosomal trafficking, causing partial albinism, neuropathy, recurrent pyogenic infections, and giant granules in leukocytes.
Hypersensitivity and Autoimmunity
Hypersensitivity questions ask for timing and effector mechanism.
| Type | Effector | Timing | Examples |
|---|---|---|---|
| I | IgE, mast cells, histamine | Minutes | Anaphylaxis, atopy, allergic asthma, urticaria |
| II | IgG or IgM against cells or receptors | Hours to days | Autoimmune hemolysis, Goodpasture syndrome, Graves disease, myasthenia gravis, acute rheumatic fever |
| III | Immune complexes with complement | 1-3 weeks | Serum sickness, systemic lupus erythematosus nephritis, poststreptococcal glomerulonephritis, Arthus reaction |
| IV | T-cell mediated inflammation | 48-72 hours | Contact dermatitis, tuberculin skin test, granulomas, type 1 diabetes |
Systemic lupus erythematosus mixes type II cytopenias with type III immune-complex disease. Anti-double-stranded DNA tracks renal involvement; anti-Smith is specific; antiphospholipid antibodies can produce thrombosis, pregnancy loss, and a false-positive non-treponemal syphilis screen. Rheumatoid arthritis has anti-cyclic citrullinated peptide antibody specificity and pannus-driven joint destruction. Goodpasture syndrome is anti-type IV collagen in glomerular and alveolar basement membranes with linear immunofluorescence.
Graves disease is a stimulatory anti-TSH receptor antibody, whereas myasthenia gravis blocks or degrades acetylcholine receptors.
Lymphoid and Myeloid Disease Clues
Hodgkin lymphoma spreads contiguously and has Reed-Sternberg cells that are usually CD15 and CD30 positive; painless lymphadenopathy, fever, night sweats, weight loss, pruritus, or alcohol-induced node pain are common clues. Non-Hodgkin lymphomas more often involve extranodal sites. Follicular lymphoma has t(14;18) causing BCL2 overexpression and impaired apoptosis. Diffuse large B-cell lymphoma is aggressive and presents as a rapidly enlarging mass. Burkitt lymphoma has MYC activation, often t(8;14), a starry-sky appearance, and very high proliferation.
Mantle cell lymphoma has t(11;14) with cyclin D1 overexpression.
Leukemia questions lean on age, cell marker, and smear. Acute lymphoblastic leukemia is common in children, has terminal deoxynucleotidyl transferase-positive lymphoblasts, and T-cell disease may form a mediastinal mass. Acute myeloid leukemia has myeloperoxidase-positive blasts and Auer rods; acute promyelocytic leukemia with t(15;17) can trigger disseminated intravascular coagulation through abnormal promyelocytes. Chronic lymphocytic leukemia is a disease of older adults with CD5-positive B cells, smudge cells, hypogammaglobulinemia, and autoimmune hemolytic anemia.
Chronic myeloid leukemia has BCR-ABL tyrosine kinase, splenomegaly, basophilia, and low leukocyte alkaline phosphatase. Hairy cell leukemia has a dry tap, splenomegaly, cytopenias, and BRAF association.
Drug and Infection Mechanisms
Immunology pharmacology is often an adverse-effect mechanism. Glucocorticoids suppress nuclear factor kappa B signaling, reduce cytokine transcription, cause neutrophil demargination, and lower lymphocytes and eosinophils. Calcineurin inhibitors such as cyclosporine and tacrolimus reduce interleukin-2 transcription and can cause nephrotoxicity. Sirolimus blocks mammalian target of rapamycin signaling downstream of interleukin-2. Mycophenolate inhibits inosine monophosphate dehydrogenase, affecting lymphocyte guanine synthesis.
Azathioprine becomes a purine analog and has toxicity risk with low thiopurine methyltransferase activity.
Biologic drugs connect directly to immune defenses. Anti-tumor necrosis factor agents can reactivate latent tuberculosis because tumor necrosis factor helps maintain granulomas. Rituximab targets CD20-positive B cells and can reactivate hepatitis B. Eculizumab blocks C5 and increases susceptibility to Neisseria. Checkpoint inhibitors remove T-cell brakes and can cause autoimmune-like endocrinopathies, colitis, dermatitis, hepatitis, or pneumonitis. Live attenuated vaccines require intact T-cell immunity, so severe T-cell immunodeficiency changes the risk-benefit logic tested in basic science vignettes.
A 7-year-old boy has recurrent liver and skin abscesses caused by Staphylococcus aureus and Serratia marcescens. Neutrophil count is normal, but dihydrorhodamine flow cytometry shows little fluorescence after stimulation. Which mechanism is defective?
Ten days after receiving a foreign antiserum, a patient develops fever, urticarial rash, arthralgias, proteinuria, and low C3. Which hypersensitivity mechanism best explains the illness?
A child has a rapidly enlarging jaw mass. Biopsy shows sheets of medium-sized lymphoid cells with a starry-sky pattern. Cytogenetic testing identifies t(8;14). Which molecular change is most directly responsible for the proliferation?