Adaptive Immunity: Cell-Mediated Immunity and Immune Disorders

Detailed Notes

12.1 Overview of Cell-Mediated Immunity

Cell-mediated immunity is the branch of the adaptive immune response driven by T lymphocytes (T cells) rather than antibodies. While humoral immunity eliminates extracellular pathogens through secreted antibodies, cell-mediated immunity targets cells that have been compromised — those infected by intracellular pathogens (viruses, certain bacteria), cancerous cells, or foreign graft tissue. The key effector cells are helper T cells (CD4+) , which orchestrate the immune response, and cytotoxic T cells (CD8+) , which directly kill abnormal cells.

The fundamental principle distinguishing T cell recognition from B cell recognition is that T cells cannot recognize free, intact antigen. They see antigen only when it has been processed into peptide fragments and displayed on the surface of another cell by major histocompatibility complex (MHC) molecules. This requirement — called MHC restriction — ensures T cells only respond to cellular threats.

12.2 T Lymphocyte Development and Selection

T cell precursors originate in the bone marrow but complete their maturation in the thymus, a primary lymphoid organ located in the mediastinum. The developmental journey through the thymus serves two critical purposes: generating a diverse repertoire of T cell receptors (TCRs) and rigorously selecting those that are useful but not self-reactive.

Stages of Thymic Development

1. Double Negative (DN) Stage: Immature thymocytes entering the thymic cortex express neither CD4 nor CD8 co-receptors (hence "double negative"). During this stage, the TCR β-chain gene undergoes rearrangement. Successful β-chain rearrangement triggers proliferation and progression.

1. Double Positive (DP) Stage: Cells now express both CD4 and CD8 co-receptors and complete rearrangement of the TCR α-chain. At this point, each thymocyte displays a unique TCR on its surface, creating an enormous diversity of antigen-recognition specificities.

1. Positive Selection: DP thymocytes interact with cortical thymic epithelial cells that express self-MHC molecules loaded with self-peptides. Only thymocytes whose TCR binds self-MHC with moderate affinity survive — this is MHC restriction. Cells that fail to recognize self-MHC at all (useless TCR) die by neglect (apoptosis). Cells that recognize MHC class I commit to the CD8+ lineage; those recognizing MHC class II commit to the CD4+ lineage. This step ensures that mature T cells will recognize antigen only when presented by the appropriate MHC class.

1. Negative Selection: Surviving single-positive thymocytes migrate to the thymic medulla and encounter medullary thymic epithelial cells (mTECs) and dendritic cells presenting a broad array of self-antigens (enabled by the transcription factor AIRE — autoimmune regulator). Any thymocyte whose TCR binds self-peptide–MHC with high affinity receives an apoptotic signal and is eliminated. This is the basis of self-tolerance — the immune system learns not to attack the body's own tissues.

Table 12.1: Stages of T Cell Development in the Thymus

Only approximately 2% of thymocytes survive both selection checkpoints. The rest undergo apoptosis and are cleared by thymic macrophages. Survivors exit the thymus as naïve T cells — immunocompetent but never having encountered their cognate antigen.

12.3 The T Cell Receptor (TCR) and MHC Restriction

TCR Structure

The T cell receptor (TCR) is a heterodimer composed of two polypeptide chains — typically α and β chains (αβ TCR, found on ~95% of T cells). A minority population bears γδ TCRs with distinct functions in barrier immunity. Each chain has a variable (V) region responsible for antigen recognition and a constant (C) region anchoring the receptor to the membrane.

The TCR alone cannot transmit signals into the cell. It is non-covalently associated with the CD3 complex, a group of invariant signaling proteins (γ, δ, ε, and ζ chains) that contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic tails. When the TCR binds its cognate peptide–MHC ligand, the CD3 ITAMs are phosphorylated by Lck (a Src-family kinase associated with CD4 or CD8 co-receptors), initiating the intracellular signaling cascade.

MHC Restriction: The Fundamental Rule

Unlike B cell receptors (antibodies) that can bind free, intact antigen in solution, the TCR cannot recognize free antigen. It only recognizes a composite ligand: a foreign peptide nestled in the peptide-binding groove of an MHC molecule. This is the principle of MHC restriction.

• MHC Class I molecules are expressed on nearly all nucleated cells. They present endogenous antigens — peptides derived from proteins synthesized inside the cell (including viral proteins and tumor antigens). MHC I presents to CD8+ cytotoxic T cells.
• MHC Class II molecules are constitutively expressed only on professional antigen-presenting cells (APCs) — dendritic cells, macrophages, and B cells. They present exogenous antigens — peptides from material the APC has phagocytosed or endocytosed. MHC II presents to CD4+ helper T cells.

Table 12.2: Comparison of MHC Class I and MHC Class II Pathways

12.4 Helper T Cells — The CD4+ Orchestra

Helper T cells (Th cells) express the CD4 co-receptor and function as the central coordinators of adaptive immunity. They do not kill directly; instead, they secrete cytokines that shape and direct the responses of other immune cells. Upon activation, naïve CD4+ T cells differentiate into distinct effector subsets determined by the cytokine milieu present during activation.

Th1 Cells — Cell-Mediated Immunity

• Polarizing cytokine: IL-12 (from dendritic cells and macrophages)
• Signature cytokine: Interferon-gamma (IFN-γ)
• Master transcription factor: T-bet
• Primary function: Activate macrophages to kill intracellular pathogens (e.g., Mycobacterium tuberculosis). IFN-γ enhances macrophage phagolysosomal fusion and production of reactive oxygen species. Th1 cells also promote CD8+ cytotoxic T cell responses and drive class switching in B cells toward opsonizing IgG subtypes.
• Clinical relevance: Th1 responses are critical for defense against intracellular bacteria, viruses, and protozoa. Defects in the Th1 pathway (e.g., IL-12/IFN-γ axis mutations) cause susceptibility to mycobacterial infections.

Th2 Cells — Humoral Immunity and Parasite Defense

• Polarizing cytokine: IL-4
• Signature cytokines: IL-4, IL-5, IL-13
• Master transcription factor: GATA-3
• Primary function: Provide help to B cells for antibody production, particularly class switching to IgE. IL-5 recruits and activates eosinophils. Th2 cells are essential for defense against helminths (parasitic worms) and are central to allergic responses.
• Clinical relevance: Overactive Th2 responses drive allergic diseases (asthma, allergic rhinitis, atopic dermatitis).

Th17 Cells — Mucosal and Barrier Immunity

• Polarizing cytokines: TGF-β + IL-6 (or IL-21)
• Signature cytokine: IL-17 (also IL-22)
• Master transcription factor: RORγt
• Primary function: Defend mucosal surfaces against extracellular bacteria and fungi (especially Candida). IL-17 recruits neutrophils to sites of infection and stimulates epithelial cells to produce antimicrobial peptides.
• Clinical relevance: Th17 cells are implicated in chronic inflammatory and autoimmune diseases including psoriasis, inflammatory bowel disease, and rheumatoid arthritis.

Regulatory T Cells (Treg) — The Brakes

• Polarizing cytokine: TGF-β (in the absence of IL-6)
• Signature cytokine: IL-10, TGF-β
• Master transcription factor: FoxP3
• Surface markers: CD4⁺ CD25⁺ FoxP3⁺
• Primary function: Suppress effector T cell responses. Tregs maintain peripheral self-tolerance by inhibiting autoreactive T cells that escaped negative selection. They also dampen immune responses after an infection has been cleared to prevent excessive tissue damage.
• Clinical relevance: Mutations in FoxP3 cause IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), a severe systemic autoimmune disease. Tregs are also exploited by tumors to evade immune destruction.

Table 12.3: CD4+ T Helper Cell Subsets and Their Characteristics

T Cell Activation: The Two-Signal Model

For a naïve CD4+ T cell to become activated, it requires two signals from an APC (typically a dendritic cell):

1. Signal 1 (Antigen recognition): The TCR binds the specific peptide–MHC II complex. The CD4 co-receptor binds MHC II, and CD3 transmits the activating signal.
2. Signal 2 (Co-stimulation): CD28 on the T cell binds B7 molecules (CD80/CD86) on the APC, which are upregulated when the APC has been activated by pathogen-associated molecular patterns (PAMPs) via innate pattern recognition receptors.

Without Signal 2, the T cell becomes anergic (functionally unresponsive) or undergoes apoptosis — a safeguard against activation by harmless self-antigens presented by resting APCs. Once fully activated, the T cell upregulates CTLA-4, which outcompetes CD28 for B7 binding and delivers an inhibitory signal, serving as a built-in off-switch.

12.5 Cytotoxic T Cells — The CD8+ Killers

Cytotoxic T lymphocytes (CTLs) express the CD8 co-receptor and are the primary killers of virus-infected cells and tumor cells.

Activation

Naïve CD8+ T cells require stronger activation signals than CD4+ cells. The classic pathway involves:

1. TCR recognition of a specific peptide presented by MHC I on the target cell or a cross-presenting dendritic cell.
2. Co-stimulation via CD28–B7 interaction.
3. CD4+ T cell help: Activated CD4+ Th1 cells "license" dendritic cells by engaging CD40 on the DC with CD40L (CD154), upregulating the DC's co-stimulatory capacity. This enables the DC to effectively prime the CD8+ T cell.

Some viruses and highly immunogenic stimuli can activate CD8+ T cells directly without CD4+ help, but CD4+ help is typically required for robust CTL responses and memory formation.

Effector Mechanisms: How CTLs Kill

Once activated, CTLs deploy a coordinated arsenal of killing mechanisms directed specifically at the target cell — a process called contact-dependent cytotoxicity:

1. Perforin–Granzyme Pathway: Upon recognizing a target cell, the CTL reorganizes its cytoskeleton to form an immunological synapse — a tight interface that focuses the release of cytotoxic granules. Perforin polymerizes in the target cell membrane, forming pores. Through these pores, granzymes (serine proteases, particularly granzyme B) enter the target cell cytoplasm. Granzyme B cleaves and activates caspase 3, triggering the apoptotic cascade. This is the major killing mechanism.

1. Fas–FasL Pathway: CTLs express Fas ligand (FasL / CD95L) on their surface. When FasL engages Fas (CD95) on the target cell, it triggers the extrinsic apoptosis pathway via caspase 8 activation. This pathway is important for eliminating activated lymphocytes during the contraction phase of an immune response and for killing cells resistant to perforin–granzyme.

1. Granulysin: A pore-forming peptide with direct antimicrobial activity, particularly against Mycobacterium tuberculosis. Granulysin can also disrupt target cell membranes and contribute to apoptosis. It is co-released with perforin and granzymes.

A single CTL can kill multiple target cells sequentially — it delivers the lethal hit, disengages, and moves on to the next target, while the condemned cell undergoes apoptosis over several hours.

12.6 Immunological Memory

Following an infection, most effector T cells die by apoptosis during the contraction phase, leaving behind a small, long-lived population of memory T cells. These cells are the basis of immunological memory — the ability to mount a faster, stronger, more effective response upon re-exposure to the same pathogen.

Types of Memory T Cells

• Central Memory T Cells (Tcm) : Express CCR7 and CD62L, homing receptors that direct them to secondary lymphoid organs (lymph nodes, spleen). Tcm cells have high proliferative capacity; upon re-encounter with antigen, they rapidly expand into a new wave of effectors. They serve as the reserve force.

• Effector Memory T Cells (Tem) : Lack CCR7 and CD62L. They circulate through peripheral tissues, positioned at frontline sites where pathogens are likely to re-enter. Tem cells can exert immediate effector function upon antigen recognition but have limited proliferative capacity. They are the rapid-response sentinels.

• Tissue-Resident Memory T Cells (Trm) : Permanently stationed in barrier tissues (skin, lung, gut mucosa) without recirculating. They provide the fastest local response to reinfection.

Table 12.4: Memory T Cell Subsets

Basis of Vaccination

Vaccination exploits immunological memory by exposing the immune system to a harmless form of a pathogen (or its components), inducing a primary adaptive response that generates pathogen-specific memory B and T cells without causing disease. Upon subsequent encounter with the real pathogen, the secondary response is:

• Faster (lag phase of hours, not days)
• Larger in magnitude (higher antibody titers, more CTLs)
• Higher affinity (due to somatic hypermutation and affinity maturation in B cells)
• Isotype-switched (IgG/IgA rather than primary IgM)

12.7 Vaccine Types

Table 12.5: Major Vaccine Platforms and Their Characteristics

Toxoid vaccines (tetanus, diphtheria) use chemically inactivated bacterial exotoxins that retain immunogenicity but have lost toxicity. Conjugate vaccines link bacterial capsular polysaccharides (T-independent antigens) to a protein carrier (e.g., tetanus toxoid), converting them into T-dependent antigens that provoke robust memory responses — essential for immunizing infants whose immune systems respond poorly to pure polysaccharides.

12.8 Hypersensitivity Reactions

Hypersensitivity refers to an excessive or inappropriate immune response that causes tissue damage. The Gell and Coombs classification divides these into four types based on the immune mechanism involved.

Type I — Immediate Hypersensitivity (IgE-Mediated)

Mechanism: On first exposure (sensitization), an allergen triggers a Th2 response, driving B cells to class-switch to IgE. IgE binds with high affinity to FcεRI receptors on mast cells and basophils, coating their surface. On re-exposure, the allergen cross-links adjacent IgE–FcεRI complexes, triggering mast cell degranulation within minutes:

• Preformed mediators (released immediately): histamine (vasodilation, increased vascular permeability, bronchoconstriction), proteases (tissue remodeling), heparin.
• Newly synthesized mediators (minutes to hours): leukotrienes (sustained bronchoconstriction — target of montelukast), prostaglandins, cytokines (IL-4, IL-5, TNF-α recruiting eosinophils for the late-phase reaction).

Clinical spectrum:

• Localized: Allergic rhinitis (hay fever), urticaria (hives), atopic asthma, food allergies (oral tingling to GI symptoms).
• Systemic anaphylaxis: Massive, widespread mast cell degranulation causing bronchoconstriction, laryngeal edema, hypotension, and shock. Can be fatal within minutes. Common triggers: peanuts, shellfish, insect stings, penicillin, latex. Treatment: intramuscular epinephrine (reverses bronchoconstriction and vasodilation).

Type II — Antibody-Mediated Cytotoxicity

Mechanism: IgG or IgM antibodies directed against antigens on cell surfaces or extracellular matrix cause damage via:

1. Complement activation (classical pathway) → membrane attack complex (MAC) lysis and opsonization (C3b).
2. Antibody-dependent cellular cytotoxicity (ADCC) : NK cells and macrophages recognize antibody-coated cells via Fcγ receptors.
3. Antibody-mediated cellular dysfunction (receptor stimulation or blockade).

Clinical examples:

• ABO transfusion reaction: Preformed IgM anti-A or anti-B antibodies bind transfused RBCs, activating complement and causing intravascular hemolysis. Presents with fever, chills, back pain, hemoglobinuria, and potentially fatal disseminated intravascular coagulation (DIC).
• Graves disease (Type II, stimulatory variant): Autoantibodies against the TSH receptor on thyroid follicular cells act as agonists, stimulating unregulated thyroid hormone production → hyperthyroidism. This illustrates that Type II can cause disease through stimulation rather than destruction.
• Myasthenia gravis (Type II, blocking variant): Autoantibodies against the acetylcholine receptor at the neuromuscular junction block neuromuscular transmission → muscle weakness.
• Goodpasture syndrome: Autoantibodies against type IV collagen in glomerular and alveolar basement membranes → glomerulonephritis and pulmonary hemorrhage.
• Autoimmune hemolytic anemia: Antibodies against RBC antigens → complement-mediated hemolysis.
• Immune thrombocytopenic purpura (ITP) : Antibodies against platelet antigens → platelet destruction → bleeding tendency.

Type III — Immune Complex-Mediated Hypersensitivity

Mechanism: Soluble antigen–antibody (immune) complexes are formed in the circulation and deposit in tissues, particularly where blood is filtered under pressure: glomeruli, joints, and small blood vessels. Deposited complexes activate complement and attract neutrophils, which release lysosomal enzymes during frustrated phagocytosis, damaging the surrounding tissue.

Clinical examples:

• Systemic lupus erythematosus (SLE) : Autoantibodies (especially anti-dsDNA and anti-nuclear antibodies / ANA) form immune complexes that deposit in kidneys (lupus nephritis), skin (malar "butterfly" rash), joints (arthritis), and serosa. Complement levels are low (consumed), which aids in diagnosis and monitoring.
• Serum sickness: A prototype Type III reaction occurring 7–10 days after administration of foreign serum (historically, horse-derived antitoxins) or certain drugs. Immune complexes deposit in vessels, joints, and kidneys → fever, rash, arthralgia, lymphadenopathy.
• Post-streptococcal glomerulonephritis: Immune complexes containing streptococcal antigens and host antibodies deposit in the glomerular basement membrane ~2 weeks after pharyngeal or skin infection → nephritic syndrome (hematuria, hypertension, edema).
• Arthus reaction: A localized Type III reaction — intradermal antigen injection in a pre-sensitized individual causes immune complex formation within the vessel wall → local vasculitis, edema, and necrosis at the injection site within 4–8 hours.

Type IV — Delayed-Type Hypersensitivity (T Cell-Mediated)

Mechanism: Unlike Types I–III (antibody-mediated, transferable by serum), Type IV is cell-mediated and delayed, peaking 48–72 hours after antigen exposure. Sensitized CD4+ Th1 cells (and sometimes CD8+ CTLs) recognize the antigen and secrete IFN-γ, activating macrophages which then cause tissue damage through the release of lysosomal enzymes, reactive oxygen species, and pro-inflammatory cytokines.

Clinical examples:

• Contact dermatitis: Small, lipid-soluble molecules (haptens) like those in poison ivy (urushiol) , nickel, latex, or cosmetics penetrate the skin, bind self-proteins, and are processed by dermal dendritic cells. Sensitized Th1 cells infiltrate the skin on re-exposure → erythema, papules, vesicles, itching.
• Tuberculin skin test (PPD): Intradermal injection of purified protein derivative from M. tuberculosis. In a previously exposed individual, memory Th1 cells infiltrate the injection site over 48–72 hours, producing a palpable induration (not just erythema). This is a classic example of diagnostic Type IV hypersensitivity.
• Graft rejection: Recognition of foreign MHC molecules on transplanted tissue by recipient T cells elicits a powerful Type IV response. Acute cellular rejection is driven by CD8+ CTLs directly killing graft cells and CD4+ Th1 cells activating macrophages. Chronic rejection involves both cellular and humoral mechanisms.
• Granulomatous inflammation: When macrophages fail to clear persistent intracellular pathogens (e.g., M. tuberculosis, Histoplasma), Th1 cells drive the formation of granulomas — organized collections of activated macrophages (epithelioid histiocytes), multinucleated giant cells, and a surrounding collar of lymphocytes. The granuloma walls off the pathogen but can cause significant tissue damage (caseous necrosis in TB).

Table 12.6: Comparison of the Four Types of Hypersensitivity Reactions

12.9 Autoimmunity

Autoimmunity arises when self-tolerance breaks down and the adaptive immune system mounts a response against self-antigens. It results from a complex interplay of genetic susceptibility (particularly HLA/MHC alleles), environmental triggers (infection, drugs, UV radiation), and defects in regulatory mechanisms.

Mechanisms of Tolerance Breakdown

1. Molecular mimicry: A pathogen expresses an epitope structurally similar to a self-antigen. The immune response against the pathogen cross-reacts with the self-antigen. Example: Rheumatic fever — antibodies against Streptococcus pyogenes M protein cross-react with cardiac myosin and valve tissue, causing pancarditis.

1. Bystander activation: Infection-induced inflammation and tissue damage release self-antigens in a pro-inflammatory context. APCs that have been activated by PAMPs can present self-antigens alongside co-stimulatory signals, breaking peripheral tolerance.

1. Epitope spreading: The initial immune response against one self-epitope causes tissue damage that exposes additional self-antigens, which then become targets (spreading the autoimmune attack).

1. Defective regulatory mechanisms: Deficiency in Treg number or function (e.g., FoxP3 mutations causing IPEX syndrome) removes a critical brake on autoreactive T cells. Defects in CTLA-4 or Fas/FasL (apoptosis pathway) also predispose to autoimmunity.

1. Release of sequestered antigens: Some self-antigens (e.g., lens crystallin in the eye, sperm antigens in the testis) are anatomically hidden from the immune system during development and were never subjected to negative selection. Trauma or inflammation exposing these "privileged sites" can trigger autoimmunity (sympathetic ophthalmia after eye trauma).

Major Autoimmune Diseases

Table 12.7: Major Autoimmune Diseases — Targets, Mechanisms, and Features

12.10 Immunodeficiency Disorders

Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or absent. It is classified as primary (congenital) or secondary (acquired) .

Primary Immunodeficiency

Primary immunodeficiencies are typically caused by single-gene mutations and often present in infancy or early childhood with recurrent, severe, or opportunistic infections.

• Severe Combined Immunodeficiency (SCID) : A heterogeneous group of disorders characterized by the absence of functional T cells, with variable B and NK cell involvement depending on the specific genetic defect.
  • X-linked SCID (most common, ~50%) : Mutation in the common gamma chain (γc) of the IL-2 receptor family (shared by IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 receptors). T⁻ B⁺ NK⁻ phenotype. Without IL-7 signaling, T cell development arrests.
  • ADA deficiency (autosomal recessive) : Deficiency of adenosine deaminase → accumulation of toxic purine metabolites (dATP) that are particularly toxic to lymphocytes. T⁻ B⁻ NK⁻ phenotype.
  • RAG1/RAG2 mutations : Defective V(D)J recombination → no functional TCR or BCR. T⁻ B⁻ NK⁺ phenotype.
  • Presentation: Severe infections in the first months of life (oral thrush, persistent diarrhea, Pneumocystis jirovecii pneumonia, failure to thrive). Live vaccines are contraindicated. Treatment: hematopoietic stem cell transplantation or gene therapy.

• DiGeorge Syndrome (22q11.2 deletion) : A developmental defect causing thymic hypoplasia or aplasia → T cell deficiency. Associated features include cardiac abnormalities (tetralogy of Fallot), hypocalcemia from parathyroid hypoplasia, and characteristic facies. Severity depends on the degree of thymic involvement.

• Bruton X-Linked Agammaglobulinemia (XLA) : Mutation in Bruton's tyrosine kinase (Btk) , essential for pre-B cell receptor signaling → arrest of B cell development. T cells are normal. Presents after ~6 months (as maternal IgG wanes) with recurrent pyogenic bacterial infections (otitis media, pneumonia, sinusitis). Treatment: intravenous immunoglobulin (IVIG).

• Common Variable Immunodeficiency (CVID) : Late-onset antibody deficiency (hypogammaglobulinemia) presenting in adults. Defective B cell differentiation into plasma cells. Recurrent sinopulmonary infections; increased risk of autoimmune disease and lymphoma.

• Chronic Granulomatous Disease (CGD) : Defect in the NADPH oxidase complex → phagocytes (neutrophils, macrophages) cannot produce the respiratory burst (reactive oxygen species) necessary to kill catalase-positive organisms. Innate, not adaptive, but classified under primary immunodeficiency. Recurrent infections with Staphylococcus aureus, Serratia, Burkholderia, Aspergillus. Diagnosis: abnormal dihydrorhodamine (DHR) flow cytometry or nitroblue tetrazolium (NBT) test.

• Leukocyte Adhesion Deficiency (LAD) : Defect in CD18 (β2 integrin) → neutrophils cannot migrate from blood into tissue (impaired adhesion and diapedesis). Presents with delayed separation of the umbilical cord, absent pus formation (neutrophils cannot reach the site), and severe periodontitis.

Secondary (Acquired) Immunodeficiency

Secondary immunodeficiency is far more common than primary and results from external factors that compromise the immune system.

• HIV/AIDS — The Prototype Secondary Immunodeficiency:
  • Causative agent: Human immunodeficiency virus (HIV) , a retrovirus that infects cells expressing CD4 and a co-receptor (CCR5 or CXCR4).
  • Target: CD4+ T cells, macrophages, and dendritic cells. Progressive depletion of CD4+ T cells is the hallmark.
  • Pathogenesis: HIV reverse-transcribes its RNA genome into DNA, which integrates into the host genome. The virus replicates actively, directly killing CD4+ T cells through cytopathic effects and indirectly through immune activation and CTL-mediated killing of infected cells. The gut-associated lymphoid tissue (GALT) is a major site of early CD4+ T cell depletion.
  • Stages:
    1. Acute infection: High viremia, flu-like syndrome; CD4 count drops transiently; seroconversion (anti-HIV antibodies) at 3–6 weeks.
    2. Clinical latency (asymptomatic) : Viral replication continues at lower levels in lymphoid tissues; CD4 count gradually declines over years (normal: 500–1500 cells/µL).
    3. AIDS: CD4+ count < 200 cells/µL and/or the development of AIDS-defining opportunistic infections or malignancies.
  • Opportunistic infections (CD4 threshold-dependent) :
    • CD4 < 200: Pneumocystis jirovecii pneumonia (PCP), Candida esophagitis
    • CD4 < 100: Cerebral toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy (JC virus)
    • CD4 < 50: CMV retinitis, disseminated Mycobacterium avium complex (MAC)
  • AIDS-defining malignancies: Kaposi sarcoma (HHV-8), non-Hodgkin lymphoma (EBV-associated), invasive cervical carcinoma.
  • Treatment: Antiretroviral therapy (ART) — combination of drugs targeting viral enzymes (reverse transcriptase, integrase, protease). ART suppresses viremia, allows CD4+ T cell recovery, and dramatically reduces morbidity and mortality but does not eradicate the latent reservoir.

• Other causes of secondary immunodeficiency:
  • Malnutrition: Protein-calorie malnutrition impairs T cell function, phagocytosis, and complement production — the most common cause of immunodeficiency worldwide.
  • Immunosuppressive drugs: Corticosteroids, calcineurin inhibitors (cyclosporine, tacrolimus), chemotherapeutic agents, biologic agents (anti-TNF, rituximab — depletes CD20+ B cells).
  • Aging (immunosenescence) : Thymic involution → reduced naïve T cell output; impaired B cell responses to new antigens; poor vaccine responses.
  • Metabolic disease: Diabetes mellitus impairs neutrophil and macrophage function.
  • Splenectomy: Loss of splenic macrophages → increased susceptibility to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis). Impaired IgM response to polysaccharide antigens.

Table 12.8: Comparison of Primary and Secondary Immunodeficiency