Norris 12 Disorders of the Immune Response, Including HIV/AIDS

What is immunodeficiency?

An abnormality in one or more parts of the immune system that results in increased susceptibility to diseases normally eliminated by a properly functioning immune response.

What is the difference between primary and secondary immunodeficiency disorders?

Primary immunodeficiencies are inherited congenital disorders; secondary (acquired) immunodeficiencies develop later in life due to other diseases or conditions.

What are the two major arms of the adaptive immune system?

Humoral (B-cell) immunity and cell-mediated (T-cell) immunity.

What is Transient Hypogammaglobulinemia of Infancy (THI)?

A temporary deficiency of immunoglobulins in infancy due to maternal IgG waning and delayed infant Ig production; usually resolves by age 3.

What causes X-linked agammaglobulinemia (XLA)?

Defect in Bruton tyrosine kinase (BTK) on Xq21.3–Xq22, leading to impaired early B-cell development and profound hypogammaglobulinemia.

What characterizes Common Variable Immunodeficiency (CVID)?

A heterogeneous humoral immunodeficiency with low IgG (often with IgA/IgM), impaired antibody responses, and recurrent infections; variable T-cell involvement.

What is Selective IgA deficiency (SIGAD) and what risk accompanies it?

Markedly reduced serum and secretory IgA with generally normal IgG/IgM; risk includes anaphylaxis to IgA-containing blood products due to anti-IgA antibodies.

What is DiGeorge syndrome and its immunologic consequence?

Chromosome 22q11.2 deletion causing thymic hypoplasia/aplasia and T-cell deficiency, with potential hypoparathyroidism and other organ defects.

What is Severe Combined Immunodeficiency (SCID)?

Profound deficiencies of T and B lymphocytes (and sometimes NK cells); varies by mutation (e.g., common gamma chain, ADA, JAK3, RAG1/2); usually fatal in infancy without reconstitution.

What is X-linked Hyper-IgM (HIGM) syndrome?

Defective CD40 signaling leading to failure of class switching (IgM high, IgG/IgA/IgE low); often due to CD40L deficiency; predominantly males.

What is Chronic Granulomatous Disease (CGD) and its key defect?

Defects in NADPH oxidase/phox subunits impair oxidative burst in phagocytes, causing susceptibility to catalase-positive bacteria/fungi and granuloma formation.

What are Leukocyte Adhesion Deficiencies (LAD)?

Primary phagocyte disorders with defective leukocyte adhesion/migration (e.g., LAD-1, LAD-2, LAD-3), leading to recurrent infections without proper neutrophil recruitment.

What is Chédiak–Higashi syndrome (CHS)?

Autosomal recessive disorder with defective lysosomal trafficking regulator (LYST), giant granules, immunodeficiency, and accelerated phase often triggered by EBV.

What is the primary problem in Wiskott–Aldrich syndrome (WAS)?

X-linked disorder due to WAS gene mutations causing eczema, thrombocytopenia, recurrent infections, and increased risk of autoimmunity and lymphoid malignancies.

What is Ataxia–telangiectasia (AT) and its immunologic features?

Autosomal recessive ATM gene mutation causing neurodegeneration, telangiectasia, Ig deficiencies, lymphopenia, cancer risk, and radiation sensitivity.

What are Combined Immunodeficiency Disorders (CIDs)?

Disorders with varying degrees of T-cell and B-cell dysfunction, less severe than SCID but with recurrent infections and other systemic issues.

What is the role of the complement system in immunity?

Innate immune component that promotes chemotaxis, opsonization, and phagocytosis; defects can cause infection risk and autoimmunity (e.g., SLE).

What is Hereditary angioneurotic edema (HAE) and its cause?

Deficiency or dysfunction of C1 inhibitor (C1-INH); autosomal dominant; causes unpredictable, potentially life-threatening angioedema.

What are primary disorders of phagocytosis and examples?

Genetic defects affecting leukocyte adhesion, degranulation, or microbicidal activity; examples include LAD, CGD, CHS.

What is graft-versus-host disease (GVHD)?

A condition where donor T cells attack recipient tissues after allogeneic stem cell transplantation, requiring depletion of donor T cells or immunosuppression.

What are the three main types of transplant rejection?

Cell-mediated (T-cell), antibody-mediated, and chronic rejection (often a mixed pattern can occur). Hyperacute, acute, and chronic forms are described.

What is the basic concept of transplant immunopathology with alloantigens?

T lymphocytes respond to donor alloantigens via direct or indirect pathways, leading to graft injury; B cells can produce donor-specific antibodies (DSAs).

What is autoimmune disease and self-tolerance?

Autoimmune diseases arise from loss of self-tolerance, leading to immune attack on host tissues; self-tolerance is maintained by central and peripheral mechanisms.

What are central and peripheral tolerance?

Central tolerance deletes autoreactive lymphocytes during maturation in primary lymphoid organs; peripheral tolerance suppresses autoreactive cells in peripheral tissues.

What are regulatory T cells (Tregs) and their role in tolerance?

CD4+CD25+ T cells that regulate antigen-specific tolerance by suppressing autoreactive T cells and inhibiting activation of naive T cells.

What is activation-induced cell death (AICD)?

Programmed death of autoreactive T cells via Fas-FasL interactions to maintain self-tolerance and prevent autoimmunity.

What mechanisms can trigger autoimmune disease beyond failure of tolerance?

Genetic susceptibility plus environmental triggers (infection, chemicals), molecular mimicry, breakdown of T-cell anergy, and superantigens.

What is the difference between autoimmune antibodies and autoantibodies?

Autoimmune diseases involve antibodies directed against self-antigens (autoantibodies) contributing to pathology; they can be detected by serology.

What viruses are linked to immune-mediated autoimmune processes via molecular mimicry?

Examples include cross-reactivity contributing to rheumatic fever after streptococcal infection and demyelination in multiple sclerosis.

What are superantigens and what do they do?

Staphylococcal/strep exotoxins that bind to a broad subset of TCRs and MHC II, causing massive, non-specific T-cell activation and cytokine release.

What is HIV and what cells does it predominantly infect?

A retrovirus that infects CD4+ T lymphocytes (and macrophages/dendritic cells), causing progressive immunosuppression.

What are the two major HIV types and where are they most prevalent?

HIV-1 is the global cause of AIDS; HIV-2 is mainly West African and progresses more slowly; most infections are HIV-1.

What is the HIV life cycle and major viral proteins involved in entry?

Attachment to CD4 receptor and chemokine co-receptors (e.g., CCR5), fusion via gp120/gp41, reverse transcription, integration, transcription, translation, proteolytic cleavage, assembly, and budding.

What are the five classes of antiretroviral drugs?

NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs, Protease inhibitors, Fusion/entry inhibitors, Integrase inhibitors (plus multidrug combinations).

What are the three phases of HIV infection?

Primary infection (acute retroviral syndrome), chronic latency, and overt AIDS with CD4+ T-cell decline and opportunistic infections.

How is HIV transmitted and what is not a mode of transmission?

Transmitted via sexual contact, blood, and perinatal routes; not transmitted by casual contact or insect vectors.

What is the window period in HIV testing?

The interval after exposure during which antibodies may be undetectable; seroconversion typically occurs within 1–3 months (can be up to 6 months).

What are common opportunistic infections in AIDS?

Fungal (eg, Pneumocystis jirovecii), viral (CMV, HSV), mycobacterial (MAC, TB), protozoal (Cryptosporidium, Toxoplasma), and bacterial infections among others.

What diagnostic methods are used to detect HIV infection?

HIV antibody testing (ELISA screening with Western blot confirmation) and PCR-based methods for HIV DNA; PCR useful in infants to detect infection.

What is perinatal HIV transmission prevention in pregnancy?

Maternal antiretroviral therapy during pregnancy and delivery, avoidance of breastfeeding when possible, and infant prophylaxis; cesarean delivery may reduce risk.

How is HIV infection diagnosed in children younger than 18 months?

Virologic assays (not antibody tests) to detect HIV DNA or RNA; two positive virologic tests from separate samples confirm infection.

What is the role of HAART in HIV management?

Highly active antiretroviral therapy—combination of three to four ARVs from different classes to suppress viral replication and preserve immune function.

What is the significance of HLA matching in organ transplantation?

Greater HLA similarity lowers rejection risk; however, even HLA-identical transplants can have GVHD, indicating minor histocompatibility differences can contribute.

What are the three forms of GVHD timing?

Acute GVHD (usually within 100 days), chronic GVHD (later), and sometimes late-onset or mixed presentations.

What is serum sickness and how is it treated?

Systemic immune complex-mediated reaction with rash, fever, arthritis after antigen exposure; treat by removing antigen and providing symptomatic care (antihistamines, steroids for severe cases).

What is the Arthus reaction?

Localized immune complex reaction causing tissue necrosis at the site of repeated antigen exposure, usually within 1 hour to 12 hours.

What are the four subtypes of Type IV hypersensitivity?

IVa (CD4+ IFN-γ–mediated; eczema), IVb (CD4+/Th2 with eosinophils), IVc (cytotoxic CD8+ T cells), IVd (neutrophil recruitment, e.g., AGEP).

What is the difference between Type II and Type III hypersensitivity?

Type II is antibody-mediated with direct tissue targeting (destruction, ADCC, receptor dysfunction); Type III involves immune complex deposition and complement activation causing inflammation.

What are examples of antibody-mediated cellular dysfunction (Type II) reactions?

Graves disease (TSH receptor activation) and myasthenia gravis (acetylcholine receptor blockade).

How are autoimmune diseases diagnosed?

Clinical history and exam plus serologic tests for autoantibodies (ELISA, indirect immunofluorescence) and correlation with symptoms; no single test is definitive.

What is the concept of immune tolerance and its two main components?

Self-tolerance maintained by central tolerance (negative selection in thymus/bone marrow) and peripheral tolerance (regulatory mechanisms and anergy).

What is the FAS/FasL pathway and its relevance to autoimmunity?

FAS receptor on activated T cells binding FasL induces activation-induced cell death (AICD) to delete autoreactive T cells and maintain tolerance.

What is the role of molecular mimicry in autoimmunity?

Infectious antigens resemble self-antigens and trigger cross-reactive immune responses that damage host tissues (e.g., rheumatic fever).

What is the basis of HIV testing in infants vs adults?

Infants rely on virologic tests (not maternal antibodies); adults rely on antibody tests (ELISA, confirmatory Western blot) since maternal antibodies are not present past 18 months.

What viral proteins are essential for HIV cell entry and infection?

gp120 and gp41 mediate attachment/fusion to CD4+ T cells; p24 is a core antigen used in screening.

What is the general course of HIV disease in terms of CD4+ T-cell decline and viral load?

High viral loads during acute infection with rapid CD4 decline, followed by a long latent period; eventual CD4 decline leads to AIDS with opportunistic infections.