21.6 Diseases Associated with Depressed or Overactive Immune Responses

Immune System Disorders

The immune system can malfunction in two broad directions: it can be too weak (immunodeficiency) or too strong (hypersensitivity and autoimmunity). Both create serious health problems. Immunodeficiencies leave you vulnerable to infections you'd normally fight off easily, while an overactive immune system damages your own tissues or reacts to harmless substances. This section covers the major categories of each.

Inherited vs. Acquired Immunodeficiencies

Immunodeficiencies fall into two groups based on their origin.

Inherited (primary) immunodeficiencies arise from genetic mutations that disrupt immune system development or function. They're present from birth.

• Severe combined immunodeficiency (SCID) involves defects in both T and B lymphocyte development. Because both branches of adaptive immunity are compromised, affected individuals are extremely susceptible to infections that healthy people handle without trouble. Without treatment (typically a bone marrow transplant), even common infections can be fatal.
• X-linked agammaglobulinemia involves a defect in B lymphocyte maturation. B cells can't develop properly, so antibody production drops dramatically. Patients experience recurrent bacterial infections, especially after about 6 months of age when maternal antibodies decline.

Acquired (secondary) immunodeficiencies develop later in life due to environmental factors, infections, or medical treatments.

• AIDS (Acquired Immunodeficiency Syndrome) is caused by HIV, which specifically infects and destroys CD4+ T helper cells. As CD4+ counts drop (healthy range is roughly 500–1,500 cells/µL; AIDS is diagnosed below 200 cells/µL), the patient becomes increasingly vulnerable to opportunistic infections like Pneumocystis pneumonia and cancers like Kaposi's sarcoma.
• Immunosuppressive therapy deliberately weakens immune responses to prevent transplant rejection or manage autoimmune diseases like rheumatoid arthritis. The trade-off is that suppressing both innate and adaptive immunity raises the risk of infections and certain cancers.

Types of Hypersensitivity Reactions

Hypersensitivity reactions are immune responses that are disproportionate or misdirected, causing tissue damage. They're classified into four types based on the mechanism involved.

Type I (Immediate) Hypersensitivity

• Mediated by IgE antibodies. On first exposure to an allergen, IgE is produced and binds to mast cells. On re-exposure, the allergen cross-links IgE on mast cells, triggering degranulation and release of histamine and other inflammatory mediators.
• Reactions occur within minutes. Examples range from allergic rhinitis (hay fever) to anaphylaxis, a life-threatening systemic reaction (e.g., to peanuts or bee stings) involving airway constriction and a dangerous drop in blood pressure.

Type II (Antibody-Mediated) Hypersensitivity

• IgG and IgM antibodies bind to antigens on cell surfaces, marking those cells for destruction through complement activation or phagocytosis.
• Examples: autoimmune hemolytic anemia (antibodies destroy red blood cells) and Graves' disease (antibodies bind TSH receptors on the thyroid, stimulating excess thyroid hormone production).

Type III (Immune Complex-Mediated) Hypersensitivity

• Antigen-antibody complexes form in the blood and deposit in tissues (often joints, kidneys, or blood vessel walls). These deposits activate the complement system, triggering inflammation and tissue damage.
• Examples: serum sickness and systemic lupus erythematosus (SLE), where immune complexes can damage multiple organ systems.

Type IV (Delayed-Type) Hypersensitivity

• The only type that does not involve antibodies. Instead, T cells (primarily CD4+ T helper cells) recognize the antigen, activate macrophages, and release cytokines that drive inflammation.
• Reactions take 24–72 hours to develop. Examples: contact dermatitis from poison ivy and the tuberculin skin test reaction.

All four types share a common theme: the immune system responds excessively or inappropriately, and the resulting damage comes from the immune response itself rather than the original antigen.

Development of Autoimmune Diseases

Autoimmune diseases occur when self-tolerance breaks down and the immune system attacks the body's own tissues. Normally, two layers of tolerance prevent this:

1. Central tolerance eliminates most self-reactive lymphocytes during development. In the thymus, T cells that strongly bind self-antigens undergo negative selection (apoptosis). A similar process occurs for B cells in the bone marrow. When this fails, autoreactive lymphocytes escape into circulation.
2. Peripheral tolerance catches autoreactive cells that slip through central tolerance. Regulatory T cells (Tregs) actively suppress these cells, and mechanisms like anergy (functional inactivation) and peripheral apoptosis serve as additional safeguards. When peripheral tolerance fails, autoreactive lymphocytes can become activated and cause disease.

Multiple Sclerosis (MS) illustrates how these failures lead to disease:

• Autoreactive T cells target myelin, the insulating sheath around nerve fibers in the central nervous system.
• Molecular mimicry may initiate the process: T cells activated by a viral antigen cross-react with myelin antigens because the two share structural similarities.
• Tregs fail to suppress these autoreactive T cells, allowing the immune attack to continue.
• The resulting inflammation and demyelination disrupts nerve signal transmission, producing symptoms like vision problems, muscle weakness, and coordination difficulties.

Autoantibodies (antibodies directed against the body's own tissues) are a hallmark of many autoimmune diseases and are often used as diagnostic markers.

Immune System Components and Processes

These core concepts connect directly to how immune disorders develop:

• Antigen-presenting cells (APCs), such as dendritic cells and macrophages, process and present antigens to T cells via MHC molecules. This step initiates adaptive immune responses and is also where self-tolerance can break down if self-antigens are presented inappropriately.
• Adaptive immunity relies on B and T lymphocytes to provide specific, long-lasting protection. Defects in either cell type underlie most immunodeficiency and autoimmune disorders discussed above.
• Inflammation is a protective innate response characterized by redness, swelling, heat, and pain. While normally beneficial, uncontrolled or misdirected inflammation is the mechanism through which hypersensitivity reactions and autoimmune diseases cause tissue damage.