12.4 Immunodeficiency Syndromes, Tumor/Transplant Immunology, and Vaccine Types

12.4 Immunodeficiency Syndromes, Tumor/Transplant Immunology, and Vaccine Types

Immunology encompasses disorders of immune deficiency, the immunologic barriers to organ transplantation, and artificial immunization through vaccination.

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Primary Immunodeficiency Syndromes (PIDs)

Primary immunodeficiencies are congenital, genetic disorders affecting specific arms of the immune system.

+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| Condition                          | Genetic / Molecular Defect  | Laboratory Findings                | Clinical Presentation & Key Features      |
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| X-Linked Agammaglobulinemia        | BTK gene mutation (Bruton   | Absent B cells (CD19/CD20-);       | Recurrent sinopulmonary bacterial/entero- |
| (Bruton XLA)                       | tyrosine kinase)            | profoundly low all Ig classes      | viral infections after 6 mos; no tonsils  |
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| Selective IgA Deficiency           | Failure of IgA B-cell       | Low/absent IgA (<7 mg/dL);         | Most common PID; mucosal infections;      |
|                                    | differentiation             | normal IgG and IgM                 | severe anaphylaxis to IgA blood products  |
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| Severe Combined Immunodeficiency   | X-linked IL-2RG defect or   | Profound lymphopenia; absent       | Failure to thrive, chronic diarrhea, thrush,|
| (SCID)                             | ADA deficiency              | T cells; absent thymic shadow      | opportunistic infections; early infant death|
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| DiGeorge Syndrome                  | 22q11.2 microdeletion       | Decreased T cells; low PTH and     | Triad: Thymic aplasia, Hypocalcemia,      |
|                                    | (3rd/4th pharyngeal pouch)  | serum calcium                      | Conotruncal heart defects (CATCH-22)      |
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| Wiskott-Aldrich Syndrome           | WAS gene X-linked mutation  | High IgE/IgA, low IgM;             | Triad (WATER): Wiskott-Aldrich, Thrombocy-|
| (WAS)                              | (actin cytoskeleton defect) | microthrombocytes (small platelets)| topenia (eczema), Recurrent infections    |
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| Hyper-IgM Syndrome                 | CD40L (CD154) gene defect   | Markedly high/normal IgM;          | Defective class switching; recurrent      |
|                                    | on CD4+ T helper cells      | low/absent IgG, IgA, IgE           | pyogenic & opportunistic (Pneumocystis) inf|
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+
| Chronic Granulomatous Disease      | NADPH oxidase subunit defect| Negative NBT dye test; abnormal    | Recurrent catalase-positive bacterial/    |
| (CGD)                              | (gp91phox X-linked)         | DHR flow cytometry assay           | fungal infections (S. aureus, Aspergillus)|
+------------------------------------+-----------------------------+------------------------------------+-------------------------------------------+

Detailed Primary Immunodeficiency Profiles

• X-Linked Agammaglobulinemia (Bruton XLA): Defect in Bruton Tyrosine Kinase (BTK) prevents pre-B cell signal transduction, halting light-chain rearrangement and B-cell maturation. Peripheral blood exhibits complete absence of mature B cells ($CD19^+, CD20^-$) and absent lymphoid tissue (tonsils, lymph node germinal centers). Maternal IgG provides protection for the first 6 months of life; thereafter, infants suffer recurrent pyogenic bacterial sinopulmonary infections (S. pneumoniae, H. influenzae) and enteroviral infections (echovirus, poliovirus).
• Selective IgA Deficiency: The most common primary immunodeficiency (~1 in 600 individuals). Characterized by severe reduction in serum and mucosal IgA with normal IgG and IgM levels. Many individuals are asymptomatic; others experience recurrent mucosal sinopulmonary infections, GI infections (Giardia lamblia), and autoimmune diseases (Celiac disease). CRITICAL PEARL: Patients develop anti-IgA antibodies and risk life-threatening anaphylaxis upon transfusion of blood products containing IgA. They must receive washed red blood cells or IgA-deficient blood.
• Severe Combined Immunodeficiency (SCID): Defect in both cell-mediated (T cell) and humoral (B cell) immunity.
  • X-Linked Recessive: Mutation in IL-2RG (common $\gamma$-chain subunit of IL-2, IL-4, IL-7, IL-9, and IL-15 receptors), impairing T-cell and NK-cell development.
  • Autosomal Recessive: Adenosine Deaminase (ADA) deficiency, leading to accumulation of toxic dATP, which inhibits ribonucleotide reductase and destroys lymphocytes.
  • Presentation: Early infant failure to thrive, persistent candidiasis (thrush), chronic diarrhea, and fatal opportunistic infections (Pneumocystis jirovecii, CMV). Chest X-ray reveals absent thymic shadow. Curative treatment requires hematopoietic stem cell transplantation (HSCT).
• DiGeorge Syndrome (22q11.2 Deletion): Microdeletion of chromosome 22q11.2 causes developmental failure of the 3rd and 4th pharyngeal pouches. Classic triad:
  1. Thymic Aplasia: Absent T-cell-mediated immunity (recurrent viral, fungal, and intracellular bacterial infections).
  2. Parathyroid Aplasia: Failure of parathyroid development causing severe hypocalcemia and neonatal tetany/seizures.
  3. Conotruncal Cardiac Defects: Tetralogy of Fallot, Truncus Arteriosus, interrupted aortic arch. (Mnemonic CATCH-22).
• Wiskott-Aldrich Syndrome (WAS): X-linked mutation in the WAS gene, impairing actin cytoskeleton reorganization required for T-cell signaling and platelet formation. Classic Triad (WATER): Wiskott-Aldrich, Thrombocytopenia (with small microthrombocytes), Eczema, and Recurrent infections. Immunoglobulin profile: elevated IgE and IgA, normal/low IgG, and low IgM.
• Hyper-IgM Syndrome: X-linked recessive defect in CD40L (CD154) on CD4+ T helper cells. T cells cannot signal B-cell CD40 to induce class switch recombination or somatic hypermutation. Laboratory findings reveal elevated or normal IgM with severely low/absent IgG, IgA, and IgE. Patients suffer recurrent pyogenic sinopulmonary infections and opportunistic infections (Pneumocystis jirovecii, Cryptosporidium).

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Transplantation Immunology

Transplant rejection is driven by host recognition of non-self HLA antigens on the donor organ.

[Transplant Rejection Spectrum]
- Hyperacute: Minutes to Hours | Pre-existing recipient antibodies | Thrombosis & Graft Ischemia
- Acute:      Weeks to Months  | Recipient CD8+ T cells or DSAs    | Vasculitis, Tubulitis, C4d+
- Chronic:    Months to Years  | CD4+ T-cell cytokines & Antibodies| Arteriosclerosis & Fibrosis
- GVHD:       Post-Bone Marrow | Donor T cells attack recipient    | Skin, Liver, GI Tract Damage

Rejection Types

• Hyperacute Rejection (Minutes to Hours): Occurs immediately upon vascular reperfusion. Driven by pre-existing recipient antibodies against donor ABO or HLA antigens (from prior blood transfusions, pregnancy, or organ transplants). Antibodies bind graft endothelium $\rightarrow$ activate classical complement $\rightarrow$ widespread endothelial thrombosis, fibrinoid necrosis, and ischemic organ death ("cyanotic graft"). Prevented by pre-transplant ABO matching and lymphocytotoxic crossmatching.
• Acute Rejection (Weeks to Months):
  • Cell-Mediated: Recipient CD8+ CTLs directly attack donor parenchymal cells, and CD4+ Th1 cells induce delayed hypersensitivity. Histology shows dense interstitial lymphocytic infiltrates, endothelialitis, and renal tubulitis.
  • Humoral (Antibody-Mediated): Recipient develops de novo donor-specific antibodies (DSAs) against donor HLA, activating complement. Histology shows neutrophil capillaritis and C4d deposition in peritubular capillaries. Reversible with high-dose corticosteroids or immunosuppressants.
• Chronic Rejection (Months to Years): Combined cellular and humoral immune response. CD4+ T cells secrete cytokines that stimulate vascular smooth muscle proliferation and intimal thickening. Results in progressive arteriosclerosis, vessel occlusion, interstitial fibrosis, and parenchymal atrophy. Manifests as chronic allograft nephropathy (kidney), accelerated graft coronary artery disease (heart), and bronchiolitis obliterans (lung). Irreversible.
• Graft-versus-Host Disease (GVHD): Occurs following allogeneic bone marrow or hematopoietic stem cell transplantation. Immunocompetent donor T cells recognize recipient host HLA antigens as foreign and launch a systemic attack. Classic target triad: Skin (maculopapular rash, desquamation), Liver (jaundice, hyperbilirubinemia, hepatomegaly), and Gastrointestinal Tract (profuse watery or bloody diarrhea, abdominal pain).

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Vaccine Types and Immunologic Mechanisms

Vaccines induce active immunity by exposing the immune system to non-pathogenic antigens, establishing long-lived memory T and B cells.

Conjugate Vaccine Immunology

Pure capsular polysaccharides (e.g., Haemophilus influenzae type b or Streptococcus pneumoniae) are T-cell-independent antigens. They cross-link B-cell receptors but cannot be presented on MHC Class II, producing only weak IgM responses without memory or affinity maturation—a major limitation in infants under 2 years old. Conjugation links the polysaccharide antigen to a strong protein carrier (e.g., diphtheria toxoid). B cells internalize the conjugate, process the protein carrier, and present carrier peptides on MHC Class II to CD4+ T cells. T-cell help stimulates B-cell class switching to IgG, producing high-affinity antibodies and long-lived memory.