Immune system - Immune Disorders

Disorders of Human Immunity Introduction The immune system normally protects the body by distinguishing between harmful foreign substances and the body's own cells and tissues. However, the immune system can malfunction in several ways. It may become weakened and fail to mount adequate defenses against pathogens—a condition called immunodeficiency. Alternatively, it may attack the body's own tissues, causing autoimmune disease. Or it may respond so vigorously to harmless substances that it damages healthy tissue, resulting in hypersensitivity reactions. This guide explores these three major categories of immune system dysfunction and the inflammatory mediators that drive many of these responses. Immunodeficiencies Immunodeficiencies are conditions in which the immune system is unable to defend the body effectively against pathogens. These can be either inherited or acquired, and they range from mild to life-threatening. Immunosenescence Immunosenescence refers to the gradual decline in immune function that occurs with aging. Beginning around age 50, the immune system becomes progressively less effective. The thymus (where T cells develop) shrinks, producing fewer new T cells. Meanwhile, the remaining T and B cells become less efficient at recognizing and responding to pathogens. This is why older adults are more susceptible to infections and respond less effectively to vaccines. Severe Combined Immunodeficiency (SCID) Severe combined immunodeficiency is a rare genetic disorder characterized by defective development of both T cells and B cells. This "combined" nature makes SCID particularly devastating—patients lack both cellular and humoral immunity. Children born with SCID are extremely vulnerable to virtually any infection, including opportunistic pathogens that would normally be harmless. Without treatment (such as gene therapy or bone marrow transplantation), SCID is typically fatal in infancy. Chronic Granulomatous Disease (CGD) Chronic granulomatous disease is an inherited disorder affecting phagocytes—specifically, neutrophils and macrophages. These cells are unable to produce reactive oxygen species (such as superoxide) needed to kill many bacteria and fungi after engulfing them. While phagocytes can still ingest pathogens through phagocytosis, they cannot effectively destroy them, leading to recurrent infections. The body attempts to contain these persistent infections by forming granulomas (nodular collections of immune cells), hence the disease's name. Acquired Immunodeficiencies Immunodeficiencies can also be acquired during a person's lifetime. The most significant example is HIV/AIDS. The human immunodeficiency virus specifically targets and destroys CD4+ helper T cells, which are central coordinators of immune responses. As these cells are depleted, both cellular and humoral immunity collapse. Additionally, certain cancers (particularly lymphomas and leukemias) can suppress immune function by directly affecting lymphocytes or interfering with bone marrow function. Autoimmunity The Problem: Loss of Self-Tolerance Autoimmune disease arises from a fundamental failure of the immune system: it loses the ability to distinguish between self (the body's own cells and molecules) and non-self (foreign pathogens). When this discrimination breaks down, the immune system attacks the body's own tissues, causing chronic inflammation and tissue damage. Central Tolerance: The Primary Defense Against Autoimmunity The body employs several mechanisms to prevent autoimmunity, the most important being central tolerance. This process occurs in two key locations: In the thymus (for T cells): Developing T cells are exposed to self-antigens presented by thymic epithelial cells and specialized cells called dendritic cells. Any T cell that binds too strongly to self-antigens is eliminated through a process called negative selection or apoptosis. Only T cells with weak or no reactivity to self-antigens survive and are released into circulation. In the bone marrow (for B cells): Similarly, developing B cells are tested against self-antigens. B cells that produce antibodies binding strongly to self-antigens are typically eliminated. This prevents the production of self-attacking antibodies. It's important to note that central tolerance is not 100% effective—some self-reactive lymphocytes do escape into circulation. The body relies on additional mechanisms called peripheral tolerance (involving regulatory T cells and immunosuppressive molecules) to control these escapees. When both central and peripheral tolerance fail, autoimmune disease develops. Common Autoimmune Diseases Several autoimmune conditions are particularly common and important to recognize: Hashimoto's thyroiditis: The immune system attacks the thyroid gland, destroying thyroid tissue and causing hypothyroidism (insufficient thyroid hormone production). Rheumatoid arthritis: Antibodies and T cells attack the synovial membranes lining joints, causing inflammation, pain, and progressive joint destruction. Type 1 diabetes mellitus: Autoimmune destruction of the insulin-producing beta cells in the pancreas results in inability to produce insulin, requiring lifelong insulin replacement. Systemic lupus erythematosus (SLE): A systemic autoimmune disease affecting multiple organs. Patients typically develop antibodies against nuclear antigens (anti-nuclear antibodies), leading to widespread immune complex deposition and inflammation in the skin, joints, kidneys, and other organs. Hypersensitivity Reactions Hypersensitivity is an immune response that, rather than protecting the body, damages host tissue. These reactions occur when the immune system responds to an antigen in a way that is excessive, misdirected, or both. Hypersensitivity reactions are classified into four types based on their immunological mechanism and timing. Type I (Immediate) Hypersensitivity Type I hypersensitivity is mediated by antibodies of the immunoglobulin E (IgE) class. Here's how it works: Initial sensitization: When a person is first exposed to an allergen (an antigen that provokes hypersensitivity), IgE antibodies specific to that allergen are produced and bind to high-affinity receptors on the surfaces of mast cells (found in tissues) and basophils (circulating white blood cells). Re-exposure and degranulation: Upon subsequent exposure to the same allergen, the allergen molecules cross-link the IgE antibodies already bound to mast cells and basophils. This cross-linking triggers rapid degranulation—the cells burst and release pre-formed inflammatory mediators stored in their granules, including histamine and heparin. Clinical manifestations: The released mediators cause immediate symptoms ranging from mild (localized itching, sneezing, runny nose) to severe. These include: Local allergic responses: allergic rhinitis, asthma, food allergies with localized symptoms Anaphylaxis: A life-threatening systemic reaction characterized by sudden onset of hypotension (dropped blood pressure), bronchospasm (airway constriction), angioedema (severe swelling), and potentially cardiovascular collapse. Anaphylaxis is a medical emergency requiring immediate intramuscular epinephrine injection. The term "immediate" refers to the rapid onset of symptoms—typically within minutes of allergen exposure. Type II (Cytotoxic) Hypersensitivity Type II hypersensitivity occurs when antibodies bind to antigens present on the surface of cells, marking those cells for destruction. The key distinction is that the targeted antigens are part of the cell itself—either native cell surface molecules or foreign antigens that have become bound to the cell surface. Mediating antibodies: The primary antibodies involved are immunoglobulin G (IgG) and immunoglobulin M (IgM). Mechanisms of cell destruction: Complement activation: When antibodies bind to cell surface antigens, they activate the complement cascade, which creates holes in the cell membrane (the membrane attack complex), causing cell lysis and death. Antibody-dependent cellular cytotoxicity (ADCC): Natural killer cells and macrophages recognize the constant (Fc) regions of antibodies bound to target cells and destroy those cells through phagocytosis or release of toxic granules. Examples of Type II hypersensitivity include hemolytic disease of the newborn (where maternal antibodies attack fetal red blood cells), transfusion reactions (when incompatible blood is transfused), and Graves' disease (where antibodies attack thyroid-stimulating hormone receptors). Type III (Immune-Complex) Hypersensitivity Type III hypersensitivity is caused by the deposition of immune complexes in tissues. Immune complexes are aggregates consisting of antigens, antibodies (primarily IgG and IgM), and complement proteins. How immune complexes cause damage: Formation: When antigen and antibody are both present in high quantities, they bind together forming large lattice-like complexes rather than being cleared efficiently. Deposition: These immune complexes circulate in the bloodstream and deposit in various tissues, particularly in blood vessel walls (where filtration occurs) and in organs like the kidney, heart, and joints. Inflammation: Once deposited in tissues, immune complexes activate the complement cascade, which produces inflammatory mediators (such as C3a and C5a). These mediators recruit large numbers of neutrophils and macrophages to the site. Tissue damage: The accumulated immune cells release enzymes and reactive oxygen species, causing inflammation and tissue destruction. Clinical examples include serum sickness (a reaction to certain medications or antiserum), systemic lupus erythematosus (where auto-antibodies against nuclear antigens form complexes), and post-streptococcal glomerulonephritis (where bacterial antigens from strep infection form complexes that deposit in kidney glomeruli). Type IV (Delayed-Type) Hypersensitivity Type IV hypersensitivity, also called cell-mediated hypersensitivity or delayed-type hypersensitivity (DTH), is fundamentally different from Types I–III in that it is not antibody-mediated. Instead, it is driven by T lymphocytes (particularly CD8+ cytotoxic T cells and CD4+ helper T cells), monocytes, and macrophages. Timeline: The reaction is termed "delayed" because symptoms typically develop 24–72 hours after exposure to the antigen, in contrast to the immediate reactions of Type I hypersensitivity. Mechanism: Sensitization: Upon first exposure to an antigen, antigen-presenting cells display the antigen to T cells, which become sensitized. Re-exposure: On subsequent exposure to the antigen, sensitized T cells recognize the antigen and become activated. They release cytokines (such as interferon-gamma) that: Activate macrophages, recruiting them to the site of antigen Cause CD8+ T cells to directly kill antigen-bearing cells Tissue damage: The accumulated and activated macrophages, along with direct T cell killing, cause inflammation and tissue destruction. Clinical examples include: Contact dermatitis: A reaction to poison ivy, nickel, or other contact allergens, manifesting as itching, redness, and blistering 1–3 days after exposure Tuberculosis skin test (Mantoux test): An induration (hardened area) appears 48–72 hours after intradermal injection of tuberculin antigen in previously sensitized individuals Graft rejection: T cells attack transplanted organs Many autoimmune diseases also involve Type IV reactions An important point: Type IV reactions do not involve IgE, histamine release, or rapid complement activation—they rely instead on cellular immunity. Inflammatory Mediators Overview of Idiopathic Inflammation Inflammation normally serves a protective purpose, helping the body defend against pathogens and repair tissue damage. However, idiopathic inflammation—inflammation occurring without a known external trigger—can become pathological. Whether triggered by infection or autoimmunity, inflammation is orchestrated by specific chemical mediators released from damaged or activated cells. Eicosanoids Eicosanoids are a class of lipid mediators derived from a 20-carbon fatty acid called arachidonic acid. Two important subclasses are: Prostaglandins: These eicosanoids have multiple roles in inflammation: Induce fever: Proslandin E2 (PGE2) acts on the hypothalamus to reset the body's temperature set-point upward Vasodilation: Prostaglandins dilate blood vessels, increasing blood flow to inflamed tissues and contributing to the redness and warmth characteristic of inflammation Pain sensitization: They sensitize nerve endings, contributing to inflammatory pain Leukotrienes: These are potent inflammatory mediators that: Attract specific white blood cells: Leukotrienes are chemotactic agents that draw neutrophils and eosinophils to sites of inflammation and infection Increase vascular permeability: They increase the leakiness of blood vessels, allowing immune cells to exit the bloodstream and enter tissues Clinically, nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen work by inhibiting the synthesis of eicosanoids, thereby reducing fever, pain, and inflammation. Cytokines: Interleukins, Chemokines, and Interferons Cytokines are soluble signaling proteins released by immune cells that regulate immune and inflammatory responses. Three major classes are particularly important: Interleukins: The term "interleukin" literally means "between white blood cells," reflecting their role in cell-to-cell communication. Interleukins facilitate communication between different types of white blood cells, coordinating immune responses. For example: IL-2 is produced by helper T cells and promotes the proliferation of cytotoxic T cells IL-4 promotes B cell differentiation into antibody-secreting plasma cells TNF-alpha (tumor necrosis factor-alpha) is a pro-inflammatory interleukin that promotes inflammation throughout the body Chemokines: Chemo (movement) + kine (protein). Chemokines are cytokines specialized for chemotaxis—directing the movement of immune cells. They establish concentration gradients from the site of inflammation outward through tissues and into the bloodstream, essentially "calling" immune cells to the injury site. For example: IL-8 recruits neutrophils RANTES attracts T cells and macrophages Interferons: These cytokines primarily have antiviral properties: Mechanism: When a cell is infected with a virus, it produces interferons that are released and bind to neighboring uninfected cells Antiviral effect: Interferons activate a pathway that shuts down protein synthesis in nearby cells, preventing viral replication Secondary effects: Interferons also increase the expression of major histocompatibility complex (MHC) molecules, making infected cells more visible to the adaptive immune system, and they activate natural killer cells to kill infected cells The combined action of these mediators—eicosanoids, interleukins, chemokines, and interferons—initiates and sustains inflammatory and immune responses, whether appropriately targeted at pathogens or inappropriately attacking self tissues.