Immunological disorders and hypersensitivities can wreak havoc on our bodies. From allergies to autoimmune diseases, these conditions occur when our immune system goes haywire, attacking harmless substances or our own tissues.

Understanding these disorders is crucial for managing health. We'll explore different types of hypersensitivity reactions, autoimmune disorders, immunodeficiencies, and how immunotherapy can help treat these conditions.

Hypersensitivity Reactions: Types and Mechanisms

IgE-Mediated Type I Hypersensitivity

• Type I hypersensitivity (immediate hypersensitivity) is mediated by IgE antibodies
• Involves the release of histamine and other inflammatory mediators from mast cells and basophils
• Triggered by the cross-linking of IgE antibodies bound to high-affinity FcεRI receptors on mast cells and basophils
• Leads to the degranulation of mast cells and basophils, releasing preformed mediators (histamine, tryptase) and newly synthesized mediators (leukotrienes, prostaglandins)
• Clinical manifestations include allergic reactions (urticaria, angioedema), anaphylaxis, and asthma

Antibody-Mediated Type II and III Hypersensitivity

• Type II hypersensitivity (antibody-mediated cytotoxicity) is caused by IgG or IgM antibodies that bind to cell surface antigens
• Leads to cell destruction through complement activation or antibody-dependent cell-mediated cytotoxicity (ADCC)
• Examples include autoimmune hemolytic anemia (antibodies against red blood cells), Graves' disease (antibodies against thyroid-stimulating hormone receptor), and myasthenia gravis (antibodies against acetylcholine receptor)
• Type III hypersensitivity (immune complex-mediated) occurs when antigen-antibody complexes deposit in tissues
• Triggers complement activation and inflammation, leading to tissue damage
• Examples include serum sickness (reaction to foreign serum proteins), systemic lupus erythematosus (SLE), and rheumatoid arthritis

T Cell-Mediated Type IV Hypersensitivity

• Type IV hypersensitivity (delayed-type hypersensitivity) is mediated by T cells
• Involves the release of cytokines that attract and activate macrophages, leading to tissue damage
• Divided into three subtypes based on the type of T cell involved and the cytokine profile:
  • Type IVa: Th1 cells secrete IFN-γ, activating macrophages (tuberculin reaction, granulomatous diseases)
  • Type IVb: Th2 cells secrete IL-4, IL-5, and IL-13, recruiting eosinophils (chronic asthma, allergic contact dermatitis)
  • Type IVc: Cytotoxic T cells directly kill target cells (contact dermatitis, graft rejection)
• Examples include contact dermatitis (reaction to skin allergens), tuberculosis (granuloma formation), and graft rejection (T cell-mediated rejection of transplanted organs)

Autoimmune Disorders: Pathogenesis and Manifestations

Pathogenesis of Autoimmune Disorders

• Autoimmune disorders occur when the immune system mistakenly attacks the body's own tissues
• Involves a complex interplay of genetic, environmental, and immunological factors
• Genetic factors: certain HLA alleles, polymorphisms in genes encoding cytokines, and immune regulators increase susceptibility
• Environmental factors: infections, drugs, and toxins can trigger autoimmunity through molecular mimicry, bystander activation, or epitope spreading
• Immunological factors: defects in central and peripheral tolerance mechanisms, impaired regulatory T cell function, and abnormal B cell activation contribute to the development of autoimmunity
• Chronic inflammation and tissue damage result from the persistent activation of autoreactive T cells and the production of autoantibodies

Clinical Manifestations of Common Autoimmune Disorders

• Rheumatoid arthritis (RA):
  • Chronic inflammatory disorder primarily affecting the joints
  • Synovial inflammation, cartilage destruction, and bone erosion
  • Symmetric polyarthritis, morning stiffness, fatigue, and extra-articular involvement (rheumatoid nodules, interstitial lung disease, cardiovascular disease)
• Systemic lupus erythematosus (SLE):
  • Multisystem autoimmune disorder characterized by the production of various autoantibodies, particularly antinuclear antibodies (ANA)
  • Formation of immune complexes that deposit in tissues, leading to inflammation and organ damage
  • Diverse clinical manifestations: malar rash, photosensitivity, arthritis, serositis, nephritis, neuropsychiatric symptoms, and hematologic abnormalities
• Multiple sclerosis (MS):
  • Chronic inflammatory demyelinating disorder of the central nervous system (CNS)
  • Activation of autoreactive T cells that cross the blood-brain barrier and attack the myelin sheath
  • Demyelination, axonal damage, and the formation of sclerotic plaques
  • Variable clinical manifestations depending on the location and extent of CNS lesions: visual disturbances, sensory and motor deficits, coordination problems, bladder and bowel dysfunction, and cognitive impairment
  • Course can be relapsing-remitting, secondary progressive, or primary progressive

Immunodeficiency: Concepts and Causes

Primary Immunodeficiencies (PIDs)

• Primary immunodeficiencies (PIDs) are caused by genetic defects that affect the development or function of various components of the immune system
• X-linked agammaglobulinemia (XLA):
  • Caused by mutations in the BTK gene, which encodes Bruton's tyrosine kinase
  • Leads to defective B cell development and antibody deficiency
  • Characterized by recurrent bacterial infections, particularly with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae)
• Severe combined immunodeficiency (SCID):
  • Caused by various genetic defects that impair the development of both T and B cells
  • Results in a lack of adaptive immunity and increased susceptibility to opportunistic infections
  • Examples include X-linked SCID (mutations in the IL2RG gene) and adenosine deaminase (ADA) deficiency
• Chronic granulomatous disease (CGD):
  • Caused by mutations in genes encoding components of the NADPH oxidase complex
  • Leads to defective phagocyte function, particularly in the generation of reactive oxygen species
  • Characterized by recurrent bacterial and fungal infections, granuloma formation, and inflammatory complications

Secondary Immunodeficiencies

• Secondary immunodeficiencies are acquired as a result of external factors, such as infections, malnutrition, or immunosuppressive treatments
• AIDS (acquired immunodeficiency syndrome):
  • Caused by HIV infection, which targets and depletes CD4+ T cells
  • Impairs cellular immunity, leading to increased susceptibility to opportunistic infections and malignancies
  • Progression marked by declining CD4+ T cell counts and the development of AIDS-defining illnesses
• Immunodeficiency associated with malnutrition:
  • Micronutrient deficiencies (zinc, vitamin A, iron) can impair various aspects of immune function
  • Protein-energy malnutrition leads to atrophy of lymphoid tissues, reduced antibody production, and impaired cell-mediated immunity
  • Increases susceptibility to infections, particularly in developing countries
• Iatrogenic immunodeficiency:
  • Caused by immunosuppressive medications (corticosteroids, chemotherapy, biologics) or radiation therapy
  • Intentional suppression of the immune system to treat autoimmune diseases, prevent graft rejection, or manage certain malignancies
  • Increases the risk of opportunistic infections and secondary malignancies

Immunotherapy: Principles and Applications

Immunotherapy in Cancer Treatment

• Immune checkpoint inhibitors:
  • Monoclonal antibodies that block inhibitory signals (CTLA-4, PD-1/PD-L1) that dampen T cell responses
  • Enhance anti-tumor immunity by releasing the brakes on T cell activation
  • Examples include ipilimumab (anti-CTLA-4), nivolumab, and pembrolizumab (anti-PD-1)
• Chimeric antigen receptor (CAR) T cell therapy:
  • Patient-derived T cells are genetically engineered to express a receptor specific for a tumor antigen
  • Expanded ex vivo and reinfused to target and destroy cancer cells
  • Approved for the treatment of certain hematologic malignancies (B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma)
• Cancer vaccines:
  • Designed to stimulate an immune response against tumor-associated antigens
  • Can be prophylactic (preventing cancer development) or therapeutic (treating existing cancer)
  • Examples include HPV vaccines (prophylactic) and sipuleucel-T (therapeutic vaccine for prostate cancer)

Immunotherapy in Autoimmune Diseases

• Biologic agents:
  • Monoclonal antibodies that target specific pro-inflammatory cytokines or their receptors
  • Reduce inflammation and tissue damage by neutralizing the effects of cytokines
  • Examples include TNF-α inhibitors (infliximab, adalimumab) for rheumatoid arthritis and Crohn's disease, and IL-6 receptor antagonists (tocilizumab) for rheumatoid arthritis
• B cell depletion therapy:
  • Monoclonal antibodies that target CD20 on B cells, leading to their depletion
  • Reduces the production of autoantibodies and modulates B cell-mediated immune responses
  • Example: rituximab for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and ANCA-associated vasculitis
• Co-stimulation blockade:
  • Fusion proteins that block the interaction between co-stimulatory molecules on T cells and antigen-presenting cells
  • Inhibits T cell activation and proliferation, reducing the inflammatory response
  • Example: abatacept for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis

Other Applications of Immunotherapy

• Allergen-specific immunotherapy (allergy shots):
  • Gradual exposure to increasing doses of allergens to induce tolerance
  • Reduces allergic symptoms and the need for rescue medications
  • Commonly used for the treatment of allergic rhinitis, allergic asthma, and venom allergies
• Monoclonal antibodies for inflammatory diseases and transplantation:
  • Infliximab and adalimumab for the treatment of Crohn's disease and ulcerative colitis
  • Basiliximab (anti-IL-2 receptor) for the prevention of acute graft rejection in kidney transplantation
  • Eculizumab (anti-C5) for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome