# Lecture 26: Immunodeficiency Disorders: Primary and Secondary

## Immunology

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## Learning Objectives

By the end of this lecture, students will be able to:

1. Distinguish primary (congenital) from secondary (acquired) immunodeficiency
2. Describe major primary immunodeficiency syndromes affecting B cells, T cells, combined, phagocytic, and complement systems
3. Explain the immunopathogenesis of HIV/AIDS including viral lifecycle, CD4+ T cell depletion, and disease progression
4. Identify the clinical patterns of infection associated with different types of immune defects
5. Discuss treatment approaches including IVIG, HSCT, gene therapy, and antiretroviral therapy

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## Lecture Content

### I. Overview of Immunodeficiency

**Immunodeficiency** is defined as impaired function of one or more components of the immune system, leading to increased susceptibility to infections and certain malignancies. **Primary immunodeficiency diseases (PIDs)** are caused by genetic defects and usually present in infancy or childhood, with more than 450 known PIDs identified to date. **Secondary (acquired) immunodeficiency** is caused by external factors including infection, drugs, malnutrition, and other conditions.

The clinical clue to immunodeficiency is recurrent, severe, unusual, or treatment-resistant infections, remembered by the mnemonic SPUR. The pattern of infections provides critical diagnostic information because it predicts which component of the immune system is defective. **B cell or antibody defects** manifest as recurrent sinopulmonary infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, as well as Giardia. **T cell defects** present with opportunistic infections including Pneumocystis jirovecii, Candida, CMV, mycobacteria, and fungi. **Phagocyte defects** produce recurrent skin and organ abscesses caused by catalase-positive organisms such as Staphylococcus, Aspergillus, and Serratia. **Complement defects** lead to Neisseria infections when terminal complement components are deficient, or SLE-like illness when early complement components are absent.

### II. Primary B Cell (Antibody) Deficiencies

**X-linked agammaglobulinemia (XLA)**, also known as Bruton's agammaglobulinemia, results from a mutation in **BTK** (Bruton's tyrosine kinase), which is essential for pre-B cell receptor signaling. Without functional BTK, B cell development arrests at the pre-B cell stage, resulting in absent mature B cells and absent immunoglobulins of all isotypes. The disease presents after 6 months of age, when protective maternal IgG wanes. Patients experience recurrent bacterial infections and have absent or hypoplastic lymph nodes and tonsils. Treatment consists of lifelong intravenous immunoglobulin (IVIG) replacement.

**Common variable immunodeficiency (CVID)** is the most common symptomatic primary immunodeficiency, occurring in approximately 1 in 25,000 individuals. It represents a heterogeneous group of disorders characterized by low IgG with low IgA and/or IgM, poor vaccine responses, and normal or reduced B cell numbers. The underlying problem is defective B cell differentiation to plasma cells, with multiple possible genetic causes including mutations in ICOS, BAFF-R, and TACI. Unlike XLA, CVID typically presents in adolescence or adulthood. Patients suffer recurrent sinopulmonary infections and face increased risk of autoimmunity, lymphoma, and granulomatous disease. IVIG is the mainstay of treatment.

**Selective IgA deficiency** is the most common primary immunodeficiency overall, occurring in approximately 1 in 500 Caucasians. It is characterized by low or absent serum IgA with normal IgG and IgM. Most affected individuals are asymptomatic, though some experience recurrent mucosal infections or develop autoimmune disease. An important clinical consideration is the risk of anaphylaxis if these patients are transfused with IgA-containing blood products, due to the development of anti-IgA antibodies.

### III. Primary T Cell and Combined Immunodeficiencies

**Severe combined immunodeficiency (SCID)**, colloquially known as "bubble boy disease," is characterized by profoundly defective T cell development, with or without B cell and NK cell involvement depending on the specific genetic defect. **X-linked SCID**, the most common form accounting for approximately 50% of cases, results from mutation in the **IL-2Rgamma chain (common gamma chain)**, which is shared by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Loss of IL-7 signaling blocks T cell development, and loss of IL-15 signaling impairs NK cell development, producing a T-B+NK- phenotype. **ADA (adenosine deaminase) deficiency** causes accumulation of toxic purine metabolites that kill lymphocyte precursors, resulting in T-B-NK- SCID. **RAG1/RAG2 deficiency** eliminates V(D)J recombination, producing T-B-NK+ SCID. Clinically, SCID presents in the first months of life with failure to thrive, chronic diarrhea, persistent oral thrush, Pneumocystis pneumonia, and an absent thymic shadow on chest X-ray. Without treatment, SCID is fatal. Hematopoietic stem cell transplant (HSCT) is curative, and gene therapy has been successful for X-linked SCID and ADA-SCID.

**DiGeorge syndrome** results from a 22q11.2 deletion causing a developmental defect of the 3rd and 4th pharyngeal pouches, leading to thymic hypoplasia or aplasia. T cell deficiency varies depending on the degree of thymic aplasia. Associated features include parathyroid hypoplasia causing hypocalcemia, cardiac defects, and facial dysmorphism. Partial DiGeorge syndrome produces mild T cell lymphopenia, while complete DiGeorge presents with a SCID-like picture.

**Wiskott-Aldrich syndrome (WAS)** is an X-linked disorder caused by mutation in the **WASP** gene, which encodes a protein involved in actin cytoskeleton regulation. It presents with the classic triad of thrombocytopenia with characteristically small platelets, eczema, and immunodeficiency affecting both humoral and cellular arms. Patients experience progressive decline in T cell function, poor antibody responses to polysaccharide antigens, and increased risk of autoimmunity and lymphoma.

**Hyper-IgM syndromes**, most commonly caused by X-linked CD40L deficiency, result from the inability of T cells to interact properly with B cells. Without CD40L-CD40 signaling, class switching and germinal center formation cannot occur, leading to normal or elevated IgM but absent IgG, IgA, and IgE. Patients are susceptible to Pneumocystis (due to impaired T cell-macrophage interaction) and bacterial infections.

<image>A diagnostic flowchart for primary immunodeficiencies. The chart begins with "Recurrent infections" and branches based on the type of pathogen. Branch 1 (Encapsulated bacteria -- S. pneumoniae, H. influenzae): leads to "B cell / antibody defect" → further branching by serum Ig levels: all Ig absent with absent B cells → XLA (BTK mutation); low IgG with present B cells → CVID; elevated IgM with absent IgG/IgA → Hyper-IgM syndrome (CD40L). Branch 2 (Opportunistic infections -- PCP, Candida, CMV): leads to "T cell defect" → absent T cells on flow cytometry → SCID (sub-branching: T-B+NK- → IL-2Rgc; T-B-NK- → ADA; T-B-NK+ → RAG1/2); low T cells with cardiac defects → DiGeorge. Branch 3 (Catalase-positive organisms -- Staph, Aspergillus, abscesses): leads to "Phagocyte defect" → abnormal DHR/NBT test → CGD (NADPH oxidase). Branch 4 (Neisseria meningitidis): leads to "Complement defect" → low CH50 → terminal complement deficiency (C5-C9). Each endpoint includes the gene defect, inheritance pattern, and treatment.</image>

### IV. Phagocyte Defects

**Chronic granulomatous disease (CGD)** results from a defect in the **NADPH oxidase** complex, which renders phagocytes unable to generate superoxide through the respiratory burst and therefore unable to kill catalase-positive organisms. The most common form is X-linked due to gp91phox mutation, with autosomal recessive forms caused by mutations in p47phox, p67phox, or p22phox. Patients develop recurrent abscesses in the skin, liver, and lung, along with granuloma formation and lymphadenopathy. Diagnosis relies on the **dihydrorhodamine (DHR) flow cytometry test** or the **nitroblue tetrazolium (NBT) test**, both of which measure the oxidative burst. Treatment includes prophylactic antibiotics (trimethoprim-sulfamethoxazole), antifungals (itraconazole), and IFN-gamma therapy, with HSCT reserved for severe cases.

**Leukocyte adhesion deficiency (LAD) type I** is caused by a defect in **CD18**, the beta2 integrin subunit, rendering LFA-1, Mac-1, and CR3 non-functional. Leukocytes cannot adhere to endothelium or transmigrate into tissues. The hallmark clinical features include delayed separation of the umbilical cord, recurrent skin infections notably without pus formation, and paradoxically high circulating neutrophil counts because the cells cannot exit the bloodstream.

**Chediak-Higashi syndrome** results from a defect in the **LYST** gene, causing abnormal lysosomal trafficking and producing giant granules in neutrophils with impaired phagolysosome fusion. Patients present with partial oculocutaneous albinism, recurrent pyogenic infections, and peripheral neuropathy.

### V. Complement Deficiencies

Deficiency of **early classical pathway components (C1q, C2, C4)** predisposes to SLE-like illness due to impaired immune complex clearance. C2 deficiency is the most common complement deficiency. **C3 deficiency** is severe, causing recurrent pyogenic infections because C3b is critical for opsonization. **Terminal pathway deficiency (C5-C9, MAC)** leads to recurrent Neisseria infections, including meningococcus and gonococcus, because the membrane attack complex is required to kill these organisms. **MBL (mannose-binding lectin) deficiency** is the most common innate immune deficiency, usually producing only mild effects with increased infections in early childhood or in immunocompromised patients. **C1 inhibitor deficiency** causes hereditary angioedema (HAE), which is not strictly an immunodeficiency but rather a dysregulated complement/kinin pathway that produces recurrent episodes of angioedema affecting the larynx, abdomen, and peripheral tissues.

### VI. HIV/AIDS: The Major Secondary Immunodeficiency

**Human immunodeficiency virus (HIV)** is a lentivirus, a type of retrovirus, that infects and destroys **CD4+ T cells**, leading to progressive immunodeficiency and ultimately AIDS. The virus carries an RNA genome in two copies along with reverse transcriptase, integrase, and protease enzymes. Its envelope glycoproteins, **gp120** (which binds CD4) and **gp41** (which mediates membrane fusion), are critical for cell entry. HIV uses **co-receptors** for entry: CCR5 for macrophage-tropic strains (R5, predominant in early infection) and CXCR4 for T cell-tropic strains (X4, which emerge in late disease). The **CCR5-delta32 mutation** renders homozygotes highly resistant to HIV infection, providing the basis for gene therapy approaches.

The **HIV lifecycle** proceeds through a series of defined steps. **Binding** occurs when gp120 engages CD4, producing a conformational change that enables gp120 to also bind its co-receptor. **Fusion** follows as gp41 mediates viral-cell membrane fusion, allowing the viral core to enter the cell. **Reverse transcription** converts viral RNA to DNA using the error-prone reverse transcriptase, which generates the high mutation rate responsible for immune evasion and drug resistance. **Integration** of viral DNA (provirus) into the host genome via integrase creates the latent reservoir. **Transcription and translation** use host machinery to produce viral proteins, enhanced by the Tat and Rev regulatory proteins. **Assembly and budding** occur at the cell membrane, with new virions acquiring their lipid bilayer envelope from the host. **Maturation** is completed when protease cleaves viral polyproteins into a mature infectious virion.

**Disease progression** follows a characteristic pattern. During **acute infection** (2 to 4 weeks), there is high viremia, a flu-like illness, and massive CD4+ T cell depletion in the gut-associated lymphoid tissue (GALT). **Clinical latency** extends for years, during which a viral set point is established and CD4+ T cells gradually decline at a rate of approximately 50 to 100 cells per microliter per year, despite continuous viral replication. **AIDS** develops when CD4 counts fall below 200 cells per microliter, at which point patients become susceptible to opportunistic infections including Pneumocystis pneumonia, toxoplasmosis, CMV retinitis, MAC, Cryptosporidium, Cryptococcus, Kaposi sarcoma, and CNS lymphoma.

The mechanisms of CD4+ T cell depletion include direct viral cytopathic effect, pyroptosis (inflammatory cell death triggered by abortive infection), CTL killing of infected cells, chronic immune activation and exhaustion, and bystander apoptosis. Treatment with combination antiretroviral therapy (cART/HAART) targets multiple steps of the viral lifecycle using NRTIs, NNRTIs, protease inhibitors, integrase inhibitors, entry inhibitors, and CCR5 antagonists. This suppresses viremia, allows immune reconstitution, and provides near-normal life expectancy.

<image>A diagram of HIV disease progression and immune response over time. The x-axis represents time (weeks for acute phase, years for chronic phase). Two y-axes: CD4+ T cell count (cells/microL, left axis) and plasma viral RNA copies/mL (right axis, log scale). Acute phase (0-12 weeks): viral load spikes sharply (reaching millions of copies/mL), CD4 count drops dramatically (especially gut CD4 depletion shown in an inset). The patient experiences acute retroviral syndrome. Anti-HIV CTL response emerges, partially controlling viremia. Anti-HIV antibodies appear (seroconversion). Chronic/latent phase (years 1-10): viral load drops to a "set point" (sustained lower level), CD4 count gradually declines over years. The patient is clinically asymptomatic or has minor symptoms. AIDS phase: CD4 drops below 200 cells/microL (dashed threshold line). Viral load rises again. Opportunistic infections are listed at this stage: PCP, toxoplasmosis, CMV, MAC, Kaposi sarcoma. An annotation shows that cART, if initiated, suppresses viral load to undetectable levels and allows CD4 recovery. A second inset shows the latent reservoir: an integrated provirus in a resting memory CD4+ T cell, explaining why HIV cannot be cured by cART alone.</image>

### VII. Other Secondary Immunodeficiencies

Beyond HIV, several other conditions produce secondary immunodeficiency. **Iatrogenic immunosuppression** from corticosteroids, chemotherapy, anti-rejection drugs (cyclosporine, tacrolimus, mycophenolate), and biologics (anti-TNF, rituximab) significantly impairs immune function. **Malnutrition** is the most common cause of immunodeficiency worldwide; protein-calorie malnutrition causes thymic atrophy, impaired T cell function, and reduced complement, while zinc deficiency specifically impairs T cell function.

**Splenectomy or functional asplenia** (as seen in sickle cell disease) removes the splenic filtration function, creating susceptibility to encapsulated bacteria including S. pneumoniae, N. meningitidis, and H. influenzae. These patients require vaccination and prophylactic antibiotics. **Malignancies** can cause immunodeficiency through various mechanisms: multiple myeloma impairs antibody production, CLL produces hypogammaglobulinemia, and Hodgkin lymphoma impairs T cell immunity. Finally, the **extremes of age** are associated with immune vulnerability: neonates have immature immune systems and rely on maternal IgG, while the elderly experience immunosenescence with reduced naive T cells, thymic involution, and impaired vaccine responses.

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