Hypersensitivity and Autoimmunity
Sometimes the immune system doesn't fail by being too weak. Instead, it overreacts or attacks the wrong targets. Hypersensitivity reactions and autoimmune diseases both represent the immune system causing harm to the body it's supposed to protect.
Mechanisms of Hypersensitivity Reactions
A hypersensitivity reaction is an exaggerated or inappropriate immune response to an antigen that results in tissue damage and inflammation. These reactions are classified into four types based on the immune mechanism involved.
Type I (Immediate) Hypersensitivity is mediated by IgE antibodies and mast cells.
- On first exposure, the immune system produces IgE antibodies that bind to the surface of mast cells.
- On re-exposure, the allergen cross-links the IgE molecules on mast cells.
- This triggers degranulation, releasing histamine, cytokines, and leukotrienes.
- These inflammatory mediators cause symptoms ranging from hives (urticaria) and asthma (bronchial constriction) to anaphylaxis, a severe, potentially fatal whole-body allergic reaction.
Type II (Antibody-Mediated) Hypersensitivity involves IgG and IgM antibodies binding directly to antigens on cell surfaces.
- The bound antibodies trigger cell destruction through complement activation or antibody-dependent cell-mediated cytotoxicity (ADCC), where natural killer cells destroy the tagged cells.
- Examples: hemolytic anemia (antibodies destroy red blood cells) and Graves' disease (antibodies mimic thyroid-stimulating hormone, causing hyperthyroidism).
Type III (Immune Complex-Mediated) Hypersensitivity occurs when antigen-antibody complexes form in the blood and deposit in tissues.
- These deposits activate complement and recruit neutrophils, leading to inflammation and tissue damage, particularly vasculitis (blood vessel inflammation).
- Examples: serum sickness (reaction to foreign serum proteins) and systemic lupus erythematosus (SLE), where immune complexes can damage the kidneys, joints, and other organs.
Type IV (Delayed-Type) Hypersensitivity is the only type that is cell-mediated rather than antibody-mediated, involving T cells instead.
- Activated T cells release pro-inflammatory cytokines (IFN-γ, TNF-α) that recruit macrophages and cause tissue damage. Symptoms take 24–72 hours to appear, which is why it's called "delayed."
- Examples: contact dermatitis (poison ivy rash) and the tuberculosis skin test, where a raised bump indicates a T cell response to tuberculin protein.
Autoimmunity and Organ Systems
Autoimmunity occurs when the immune system loses self-tolerance and begins attacking the body's own tissues. Normally, immune cells that react to self-antigens are eliminated or suppressed during development. When this process breaks down, the result is autoantibodies or self-reactive T cells that cause chronic inflammation and tissue damage.
Several factors contribute to autoimmunity: genetic predisposition (certain HLA gene variants increase risk), environmental triggers (infections, toxins), and hormonal factors (autoimmune diseases are more common in women).
Organ-specific autoimmune diseases target a particular tissue or organ:
- Type 1 diabetes: T cells destroy insulin-producing beta cells in the pancreas, leading to insulin deficiency and hyperglycemia.
- Hashimoto's thyroiditis: Autoantibodies attack the thyroid gland, gradually destroying it and causing hypothyroidism (underactive thyroid).
- Multiple sclerosis: The immune system damages the myelin sheaths that insulate neurons in the central nervous system, disrupting nerve signal transmission and causing neurological symptoms.
Systemic autoimmune diseases affect multiple organ systems:
- Rheumatoid arthritis: Autoimmune inflammation targets the synovial lining of joints, causing pain, swelling, and progressive joint deformity.
- Systemic lupus erythematosus (SLE): Can affect the skin (butterfly rash), joints (arthritis), kidneys (nephritis), and brain (neuropsychiatric symptoms). This is also a Type III hypersensitivity disease due to immune complex deposition.
- Scleroderma: Autoimmune-driven fibrosis (excess collagen deposition) hardens the skin and can damage internal organs including the lungs, gastrointestinal tract, and heart.
Immunodeficiency
When the immune system is weakened or absent, the body becomes vulnerable to infections it would normally fight off easily. Immunodeficiencies are divided into two categories based on their origin.
Primary Immunodeficiencies
These are genetic disorders present from birth that affect immune system development or function.
- Severe combined immunodeficiency (SCID): Defects in both T and B cell development leave patients with virtually no adaptive immunity. Without treatment, even common viral, bacterial, and fungal infections can be life-threatening. This is sometimes called "bubble boy disease."
- X-linked agammaglobulinemia: B cells fail to develop, so the body cannot produce antibodies. Patients experience recurrent bacterial infections such as pneumonia and ear infections (otitis media).
- Chronic granulomatous disease (CGD): Phagocytes cannot generate the reactive oxygen species needed to kill engulfed pathogens. This leads to recurrent fungal infections (Aspergillus) and bacterial infections (Staphylococcus).
Secondary Immunodeficiencies
These are acquired conditions that compromise immune function later in life.
- HIV/AIDS: The human immunodeficiency virus specifically targets and depletes CD4+ T helper cells. As CD4+ counts drop, the immune system progressively fails, leaving patients susceptible to opportunistic infections like Pneumocystis pneumonia and Candida esophagitis.
- Malnutrition: Protein-energy malnutrition impairs immune cell production and function. This is a major cause of immunodeficiency worldwide.
- Immunosuppressive medications: Drugs used to prevent organ transplant rejection or treat autoimmune diseases deliberately suppress immune responses, which increases infection risk as a side effect.
- Cancer and its treatments: Both the disease itself and therapies like chemotherapy and radiation can destroy immune cells, leaving patients more vulnerable to infections.
Consequences of Immunodeficiency
Regardless of the cause, immunodeficiency leads to:
- Increased frequency and severity of infections
- Infections caused by organisms that rarely affect healthy people (opportunistic infections)
- Delayed wound healing and prolonged illness
- Higher risk of certain cancers, particularly lymphomas and Kaposi's sarcoma (especially in HIV/AIDS patients)
Immune System Components
Understanding disruptions in immunity requires knowing how the normal system works. The immune system has two major branches that work together.
Types of Immunity
Innate immunity is the first line of defense and responds within minutes to hours.
- Physical barriers: Skin and mucous membranes block pathogen entry.
- Chemical barriers: Stomach acid, lysozyme in tears, and antimicrobial peptides destroy pathogens.
- Cellular components: Neutrophils and macrophages engulf and destroy pathogens through phagocytosis.
- Innate immunity responds quickly and broadly but lacks specificity. It does not "remember" previous infections.
Adaptive immunity develops more slowly (days to weeks on first exposure) but provides targeted, long-lasting protection.
- Antigen-presenting cells (like dendritic cells) process pathogens and display their antigens to activate lymphocytes.
- B lymphocytes produce antibodies that neutralize pathogens and mark them for destruction. This is humoral immunity.
- T lymphocytes directly kill infected cells (cytotoxic T cells) and coordinate immune responses (helper T cells). This is cell-mediated immunity.
- Adaptive immunity generates memory cells, which is why you typically don't get the same illness twice and why vaccines work.