Immune Disorders U3C

Disorders of the Immune Response

  • The immune system can become inefficient (immunodeficiency) or hyperactive (hypersensitivity/autoimmunity), leading to debilitating or life-threatening diseases.

    • Disease processes include immunodeficiency disorders, allergic or hypersensitivity reactions, autoimmune disorders, and transplant rejection.

    • Etiologies: Often traced to abnormalities in cellular (T cells, B cells, phagocytes) or chemical (cytokines, complement) components of the innate and adaptive immune responses.

Immune System Overview

  • The innate and adaptive immunity systems work in a coordinated fashion to protect the body.

    • Innate Immune System:

      • First line of defense: Employs rapid, nonspecific responses.

      • Components: Phagocytic leukocytes (neutrophils, macrophages), natural killer (NK) cells, and chemical mediators like chemokines and cytokines (e.g., $IL-1$, $IL-6$, $TNF-\alpha$).

      • The Complement System: A cascade of proteins that enhance (complement) the ability of antibodies and phagocytic cells to clear microbes. Primary pathways include the Classical, Lectin, and Alternative pathways.

    • Adaptive Immune System:

      • Specificity and Memory: Develops more slowly but targets specific epitopes. It "remembers" prior exposures for faster subsequent responses.

      • Humoral Response: Mediated by B lymphocytes that transform into plasma cells to produce antigen-specific immunoglobulins (IgG, IgA, IgM, IgE, IgD) and memory B cells.

      • Cell-mediated Response: Mediated by T lymphocytes. CD4^{+} helper T cells coordinate the response by releasing cytokines, while CD8^{+} cytotoxic T cells directly kill infected or malignant cells.

Immunodeficiency Disorders

Definition and Classification

  • Immunodeficiency: An abnormality in one or more components of the immune system that renders a person susceptible to diseases normally suppressed by a healthy immune response.

  • Classifications:

    • Primary (Congenital): Result from genetic defects, typically manifesting in infancy. Many are $X$-linked or autosomal recessive.

    • Primary Immunodeficiency Disorder (PID)→ deficient in antibodies, autosomal recessive, inherited

      • Seen in children→ look for frequent infections

        • Especially resp infections that are not common in children

    • Secondary (Acquired): Occur later in life due to external factors such as malnutrition, viral infections (e.g., $HIV$), cancers (e.g., Hodgkin’s Lymphoma), or medical treatments (e.g., chemotherapy, corticosteroids).

Humoral (B-cell) Immunodeficiencies

  • Primarily involve impaired antibody production. Individuals are prone to recurrent infections by encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae).

    • Primary Examples:

      • X-linked Agammaglobulinemia (Bruton’s): A defect in $B$-cell maturation where $B$ cells do not progress beyond the pre-$B$ stage.

      • Selective $IgA$ Deficiency: The most common primary immunodeficiency; often asymptomatic but can cause respiratory and gastrointestinal infections.

    • Secondary Examples: Chronic lymphocytic leukemia (CLL) or nephrotic syndrome (loss of IgG in urine).

Cellular (T-cell) Immunodeficiencies

  • Often more severe than B-cell deficiencies because T cells are required for both cellular and humoral immunity orchestration.

  • Primary Cell-mediated Immune Disorders

    • usually deadly, mother IgG antibodies don’t help

    • children who live need bone marrow transplant

      • DiGeorge Syndrome (22q11.2 Deletion):

        • Characterized by the mnemonic CATCH-22: Cardiac defects, Abnormal facies, Thymic hypoplasia/aplasia, Cleft palate, Hypocalcemia (due to parathyroid hypoplasia), and deletion of chromosome 22.

        • Need bone marrow tx to live out of childhood

        • The lack of a thymus leads to a profound deficit in mature T cells.

      • Secondary Causes: More common. Viral infections (Measles, HIV) or cancer which transiently or permanently suppress T-cell function.

Combined B-cell and T-cell Immunodeficiencies

  • Severe Combined Immunodeficiency (SCID): No T or B cells. Fatal within the first 22 years of life without a bone marrow transplant or gene therapy.

  • Combined Immunodeficiency→ some T and B, lots of infections, usually die kinda young

Phagocytosis

  • Secondary: DM type 1 → body produces antibodies against its own tissues

  • People affected by phagocytic disorders are susceptible to bacterial and fungal infections

    • elderly

    • antibiotic use→ eliminated health flora, ex: Candida

Hypersensitivity

→ disorders caused by the body’s immune response, over-reaction

Disorders

Classifications

  • Type I (Immediate): IgE-mediated. Rapid. Allergens bind to IgE on mast cells and basophils, causing degranulation and release of histamine and leukotrienes.

    • Anaphylaxis: A systemic Type I reaction. Causes massive vasodilation (hypotension) and bronchoconstriction (respiratory distress). Edema and shock→ IgE. Treatment: Epinephrine.

    • Histamine→ main mediator in T1 reaction→ asthma

    • Classic response→ coughing, sneezing, watering eyes

    • Atopic/Local reaction: urticarial (hives), Allergic rhinitis, dermatitis, asthma

    • Food allergies→ IgE antibody in GI→ systemic histamine

      • peanuts, tree-nuts, and shellfish

  • Type II (Antibody-mediated): IgG or IgM antibodies directed against target antigens on specific host cell surfaces or tissues. Examples include mismatched blood transfusion reactions and Hemolytic Disease of the Newborn.

  • Type III (Immune Complex-mediated): Formation of antigen-antibody complexes that circulate and deposit in tissues (e.g., kidneys, joints), triggering complement activation and inflammation. Example: Systemic Lupus Erythematosus (SLE) or Serum Sickness.

  • Type IV (Cell-mediated): Delayed hypersensitivity involving sensitized T cells rather than antibodies. Examples: Contact dermatitis (poison ivy) and the Tuberculin (PPD) skin test (24-72 hour peak response).

    • Allergic contact dermatitis→ poison ivy 24-48 hours after exposure

    • Most latex reactions (rest are type 1)

      • Dx: Latex-specific serum IgE immunoassays

Autoimmune Disease

→body produces antibodies against its own tissues

→ effects women more than men

  • Mechanism: A breakdown in self-tolerance, where the immune system fails to distinguish between self-antigens and foreign antigens and mounts an immune response against host tissues

  • Immunologic Tolerance→ self-regulatory action that identifies self and not attacking

    • Molecular Mimicry: A foreign antigen resembles a self-antigen, causing the immune system to attack both (e.g., Rheumatic Fever after Strep infection).

    • Genetic Predisposition: Often linked to specific HLA (Human Leukocyte Antigen) types.

HIV and AIDS

  • HIV (Human Immunodeficiency Virus): A retrovirus that infects CD4+ cells.

  • breaks down immune system, neuro, muscle, opportunistic infections

  • HIV 1 causes AIDS, HIV 2 does not

  • Sex is the most common transmission, especially with other present STI infections

  • Vertical transmission→ most common etiology for HIV in children

    • in-utero, during labor and birth, or breastmilk

    • Lifecycle:

      1. Binding/Fusion: GP120$ and $GP41$ viral proteins bind to $CD4$ and coreceptors ($CCR5$ or $CXCR4$).

      2. Reverse Transcription: Viral $RNA$ is converted to $DNA$ by Reverse Transcriptase.

      3. Integration: Viral $DNA$ is inserted into the host genome by Integrase.

      4. Replication and Budding: New virions are assembled and released.

  • Clinical Progression:

    • Stage 1 (Acute): High viral load, flu-like symptoms, 2-4 weeks after exposure

    • Stage 2 (Latent): Low viral replication, asymptomatic, can last 88-1010 years.

      • Lymphadenopathy→ swollen lymph nodes in cervical, axilla, and inguinal regions

    • Stage 3 (AIDS): Defined by CD4+ count < 200200 cells/μ L or an AIDS-defining opportunistic infection (e.g., Pneumocystis jirovecii pneumonia, Kaposi Sarcoma).

      • Opportunistic infections→ don’t normally cause infection unless compromised

        • Cytomegalovirus (CMV)→ KNOW THIS

  • HIV/AID Clinical Manifestations

    • Diarrhea→ very common

    • Staph aureus skin infections

    • Kaposi sarcoma→ anyone dx with this needs a HIV screen

    • CNS infections