Disorders of the Immune Response, Including HIV/AIDS

Classification of Immunodeficiency States

Immunodeficiency states are conditions in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. These can be classified as:

• Primary (Congenital or Inherited): Caused by genetic defects affecting B-cell, T-cell, or immunoglobulin function. Often detected in infancy or childhood due to repetitive infections.

• Secondary (Acquired): Develops later in life due to factors such as malnutrition, infection (e.g., Acquired Immunodeficiency Syndrome [AIDS]), neoplastic diseases (e.g., lymphoma), or immunosuppressive therapy (e.g., corticosteroids, transplant rejection medications).

Results of Alterations of the Immune System

Alterations in immune function can lead to several clinical outcomes:

• Immunodeficiency States: Weak or dysregulated immune system, increasing susceptibility to infections and chronic inflammation (e.g., asthma, bowel disease, heart disease).

• Allergic / Hypersensitivity Reactions: Overreaction of the immune system to harmless substances, resulting in allergic reactions.

• Transplant Rejection: Immune system attacks transplanted tissue, recognizing it as foreign.

• Autoimmune Disorders: The body attacks its own cells, often with B-cell overactivity, excessive antibody production, and tissue damage. Genetic risk factors may increase susceptibility.

Major Categories of Immune Mechanisms

Overview of Immune Mechanisms

The immune system employs several mechanisms to defend against pathogens:

• Humoral (Antibody-Mediated) Immunity: B lymphocytes produce antibodies that defend against extracellular microbes and toxins.

• Cell-Mediated Immunity: T lymphocytes (helper and cytotoxic) defend against intracellular microbes.

• Complement System: A group of proteins in blood that form the first line of defense. Activation leads to bacterial aggregation and increased susceptibility to phagocytosis.

• Phagocytosis: Neutrophils and macrophages engulf and destroy pathogens.

Immunodeficiency Disorders

Humoral Immunodeficiencies

Humoral immunity is a component of adaptive immunity, primarily mediated by B cells and antibodies.

• Deficiency Effects: Impaired B-cell function and antibody production increases risk of recurrent bacterial infections (e.g., pneumonia, bronchitis, sinusitis, GI infections).

• Less Important for: Defense against intracellular bacteria (e.g., Mycobacterium tuberculosis), fungi, protozoa.

• Viral Control: Most viruses are controlled except enteroviruses (GI infections).

Primary Humoral Immunodeficiency Disorders (PHIDs)

PHIDs are genetic disorders affecting B lymphocytes and account for approximately 70% of primary immunodeficiencies.

• Normal Antibody Production Requires:

  • Stem cells that mature into B cells (recognize and fight bacteria/viruses).

  • Plasma cells (from B cells) that produce immunoglobulins (antibodies) in bone marrow, lymph nodes, and spleen.

• PHID Problem: Disruption of antibody production, affecting one or more types of immunoglobulins.

Disorders of the Complement System

The complement system is crucial for fighting infection and clearing cellular debris.

• Primary (Genetic): Usually autosomal recessive; missing one or more complement proteins; may overlap with secondary disorders.

• Secondary (Acquired): Caused by diseases that weaken immunity (e.g., Systemic Lupus Erythematosus [SLE]).

• Hereditary Angioedema: Rare genetic disorder due to lack of C1-inhibitor protein, causing recurrent swelling (hands, feet, face, airway, abdomen).

Dysfunction of the Phagocytic System

Phagocytic dysfunction increases susceptibility to bacterial and fungal infections.

• Causes: Defective phagocyte function or low phagocyte numbers.

• Susceptibility: Candida albicans (yeast), filamentous fungi.

• Example: Chronic Granulomatous Disease (CGD) – defective phagocytes lead to recurrent infections.

Hypersensitivity Disorders

Definition and Types

Hypersensitivity disorders are characterized by excessive or inappropriate activation of the immune system.

• Type I: IgE-mediated disorders

• Type II: Antibody-mediated disorders

• Type III: Complement-mediated immune disorders

• Type IV: T-cell-mediated disorders

Types of IgE-Mediated Allergic Reactions

• Atopic Disorders: Genetic predisposition; overactive immune system produces high levels of IgE in response to common allergens (e.g., pollen, dust mites, pet dander). Examples: urticaria (hives), allergic rhinitis (hay fever), atopic dermatitis (eczema), food allergies, some forms of asthma.

• Nonatopic Disorders: No genetic predisposition, but increased risk of developing allergic reactions.

Phases of Type I Hypersensitivity Reactions

• Primary (Immediate) Response: Rapid onset (minutes); effects include vasodilation, vascular leakage, smooth muscle contraction. Examples: anaphylaxis, allergic rhinitis, allergic asthma.

• Secondary (Late) Response: Occurs hours later; involves infiltration of eosinophils and other immune cells, tissue damage (epithelial injury). Examples: persistent allergic asthma, atopic dermatitis (eczema).

• Treatment (Mild Cases): Corticosteroids and immunosuppressants.

Type II (Cytotoxic) Hypersensitivity Reactions

Antibodies target antigens on surface cells, leading to cell destruction.

• Examples: Mismatched blood transfusion reactions, hemolytic disease of the newborn, certain drug reactions.

• Mechanism: Antibody binding leads to cell lysis or dysfunction (e.g., Graves disease – antibodies bind to TSH receptor).

Type III, Immune Complex Allergic Disorders

Immune complexes (antigen-antibody clumps) form and deposit in blood vessels or tissues, triggering the complement system and inflammation.

• Damage: Alters blood flow, increases vessel permeability, causes tissue injury.

• Systemic Reactions:

  • Serum sickness: Immune complexes deposit in many tissues (fever, rash, joint pain).

  • Systemic lupus erythematosus (SLE): Autoantibodies (anti-DNA) form immune complexes causing widespread inflammation.

  • Rheumatoid arthritis (RA): Complexes deposit in joints (swelling, pain, joint damage).

• Localized Reaction: Arthus reaction – localized inflammation after injection or vaccine (redness, swelling, tissue damage).

Type IV Hypersensitivity Reactions

T-cell response to microorganisms, chemicals, or self-antigens can cause cell death and tissue injury.

• Direct Cell-Mediated Cytotoxicity: Example: Hepatitis (T-cells kill infected cells).

• Delayed-Type Hypersensitivity: Example: Contact dermatitis (poison ivy, drug reactions), hypersensitivity pneumonitis (lung inflammation from inhaled antigens).

Transplantation Immunology

Histocompatibility Complex

The major histocompatibility complex (MHC) is essential for distinguishing self from nonself and initiating immune responses.

• Functions: Lymphocyte recognition, antigen presentation, control of immune response.

Categories of Transplanted Tissue

Stem Cell Transplantation

Stem cell transplantation can cure certain genetic immune disorders (e.g., SCID, Wiskott-Aldrich syndrome, chronic granulomatous disease).

• Donor stem cells repopulate the bone marrow and produce new, healthy immune cells.

• Patient's bone marrow is destroyed with chemotherapy before transplant to allow new cells to grow.

Patterns of Transplant Rejection

Graft-versus-Host Disease (GVHD)

GVHD occurs when donor immune cells attack the recipient's tissues.

• Transplant must have a functional cellular immune component.

• Recipient tissue must bear antigens foreign to donor tissue.

• Recipient immunity must be compromised so it cannot destroy transplanted cells.

Autoimmune Diseases

Overview and Examples

Autoimmune diseases result from the immune system attacking the body's own tissues. Treatment aims to suppress immune responses and reduce inflammation, often using corticosteroids or immunosuppressants.

• Systemic Lupus Erythematosus (SLE): Affects skin, joints, kidneys, lungs, heart, brain; symptoms include butterfly rash, joint pain, and flares/remission.

• Autoimmune Hemolytic Anemia (AIHA): Immune system destroys red blood cells, leading to anemia (fatigue, weakness, pale skin).

• Pemphigus Vulgaris: Rare blistering disease of skin and mucous membranes; immune system attacks proteins that keep skin cells together.

• Hashimoto Thyroiditis: Immune system attacks thyroid gland, causing hypothyroidism; symptoms include fatigue, weight gain, cold intolerance.

Mechanisms of Autoimmune Disease

• Heredity (Genetics): Problems with HLA (human leukocyte antigens) reduce self-tolerance.

• Gender: More common in women due to sex hormones and X chromosome genes.

• Failure of Self-Tolerance: Immune system cannot distinguish self from non-self.

• MHC Disorders: Problems with MHC-antigen receptor interactions.

• Molecular Mimicry: Pathogen proteins resemble self-proteins, leading to immune attack on body's own cells.

• Superantigens: Pathogens release superantigens that overactivate immune cells, causing massive cytokine release and potentially toxic shock.

HIV/AIDS: Pathophysiology, Transmission, and Clinical Course

The AIDS Epidemic and Transmission of HIV Infection

HIV is an RNA retrovirus that destroys CD4+ T cells, impairing cell-mediated immunity.

• Transmission: Sexual contact, blood-to-blood contact, perinatal transmission (reduced by C-section and avoiding breastfeeding).

• Mother-to-infant transmission is the most common route for children.

Pathophysiology and Clinical Course

• HIV Structure: Enveloped virus with single-stranded RNA genome; reverse-transcribed into DNA upon entry into host cell, integrating into host genome and persisting in CD4 cells.

• Phases of HIV Infection:

  1. Acute Primary Infection: 2-4 weeks; flu-like symptoms; rapid HIV multiplication; increased risk of transmission.

  2. Chronic Asymptomatic/Latency Phase: Can last years/decades; low viral replication; no symptoms; can progress to AIDS if untreated.

  3. Overt AIDS Phase: Severe immune damage; opportunistic infections; CD4 cell count below 200 cells/mm3; death due to infections.

Clinical Manifestations of HIV/AIDS

• Opportunistic Infections: Pneumocystis pneumonia (PCP), toxoplasmosis, cryptococcal meningitis.

• Respiratory: Cough, shortness of breath.

• Gastrointestinal: Persistent diarrhea.

• Nervous System: Headaches, seizures.

• Cancers: Skin lesions, Kaposi sarcoma.

Prevention, Diagnosis, and Treatment of HIV/AIDS

• Prevention: Safe sex, pre-exposure prophylaxis, needle exchange programs, HIV testing, male circumcision, HIV education.

• Diagnostic Methods:

  • Enzyme immunoassay (ELISA): Detects and quantifies specific antibodies or antigens in a sample.

  • Western blot antibody detection: Used to confirm HIV infection by identifying specific proteins; commonly used as a confirmatory test after a positive ELISA.

• Treatment:

  • Reverse transcriptase inhibitors (RTIs): Antiretroviral drugs that block viral replication.

  • Protease inhibitors: (e.g., atazanavir, darunavir, fosamprenavir, lopinavir) block viral protein processing.

  • Fusion inhibitors: Prevent HIV from entering human cells.

Key Equations and Concepts

• CD4 Cell Count Threshold for AIDS Diagnosis: