Alterations in Immunity and Inflammation

Overview of Altered Immune Responses

Allergy: An exaggerated or inappropriate immune response directed against an environmental antigen (allergen) that is normally harmless.
Autoimmunity: A misdirected immune response where the host's immune system loses self-tolerance and attacks its own healthy cells and tissues.
Alloimmunity (Isoimmunity): An immune response directed against beneficial foreign tissues from another individual of the same species (e.g., blood transfusion reactions, organ transplant rejections, or transient neonatal alloimmunity).
Severity: All three types of altered immune responses can range from mild discomfort to severe, life-threatening clinical conditions.

General Concepts of Hypersensitivity

Definition: Hypersensitivity is an altered immunologic reaction to an antigen that results in pathological damage or disease to the host upon re-exposure.
Three Key Variables in Hypersensitivity:
- Original Insult: The primary event that disrupts immunologic homeostasis (the steady-state tolerance to self-antigens or lack of response to non-harmful environmental antigens).
- Genetic Makeup: Individual genetic variation determines the susceptibility, intensity, and nature of the immune response to the insult.
- Immunologic Process: The specific cellular and molecular immune pathway that ultimately causes host tissue injury and clinical disease symptoms.
Temporal Characteristics and Sensitization:
- Sensitization: The initial exposure to an antigen that induces a primary immune response, producing a threshold level of antibodies or T cells. Noticeable hypersensitivity reactions occur only upon subsequent re-exposure to the same antigen.
- Immediate Hypersensitivity Reaction: A reaction that develops within minutes to a few hours following re-exposure. Anaphylaxis is the most extreme form and can be localized (cutaneous) or systemic.
- Delayed Hypersensitivity Reaction: A cell-mediated reaction that takes several hours to manifest, reaching peak severity days after re-exposure.
Anaphylaxis:
- The most rapid and severe immediate hypersensitivity response, occurring within minutes of re-exposure.
- Clinical manifestations include:
- Pruritus (itching)
- Erythema (redness)
- Headaches
- Bronchoconstriction and contraction of respiratory bronchioles
- Laryngeal edema
- Gastrointestinal distress (vomiting, abdominal cramps, diarrhea)
- Systemic vascular collapse and hypotension
- Common triggers include bee stings, peanuts, eggs, shellfish, and specific medications.
- Emergency administration of epinephrine (e.g., EpiPen Auto-Injector, $0.3\,\text{mg}$ dose) acts to reverse bronchoconstriction and vasodilation.

Type I Hypersensitivity: IgE-Mediated Reactions

Mechanism: Mediated by Immunoglobulin E (IgE) antibodies produced in response to environmental allergens.
Pathophysiology:
- Allergen triggers B-cell activation and class switching to IgE.
- The crystallizable fragment (Fc) portion of IgE binds high-affinity Fc receptors on the surface of tissue mast cells and circulating basophils (cytotropic antibodies).
- Re-exposure causes antigen cross-linking of surface-bound IgE molecules, triggering cell activation and degranulation.
Chemical Mediators:
- Primary Mediators (Pre-formed Granule Contents):
- Histamine
- Proteases
- Chemotactic factors: Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A) and Neutrophil Chemotactic Factor (NCF).
- Secondary Mediators (Newly Synthesized Membrane Lipid Metabolites):
- Phospholipase $A_2$ activation converts membrane phospholipids into arachidonic acid.
- Leukotrienes ( $B_4, C_4, D_4$ ): Induce prolonged bronchoconstriction and vascular permeability.
- Prostaglandins (Prostaglandin $D_2$ ): Cause vasodilation and pain.
- Platelet-Activating Factor (PAF).
Histamine Receptors:
- $H_1$ Receptors: Cause bronchial smooth muscle contraction (bronchospasm), endothelial cell contraction leading to edema, and vasodilation.
- $H_2$ Receptors: Increase gastric acid secretion and provide negative feedback to inhibit further histamine release from mast cells and basophils.

Type II Hypersensitivity: Tissue-Specific Reactions

Definition: Hypersensitivity reactions targeting antigens localized to specific cells or tissues (tissue-specific antigens).
Five Mechanisms of Type II Tissue Damage:
1. Complement-Mediated Lysis: Antibodies (IgG or IgM) bind target cell surface antigens and activate the classical complement cascade, leading to membrane attack complex (MAC) assembly and cell lysis.
2. Phagocytosis via Opsonization: IgG antibodies bind cell antigens and engage $Fc\gamma$ receptors on macrophages, or complement component $C3b$ binds and engages $C3b$ receptors, triggering target cell phagocytosis.
3. Neutrophil-Mediated Damage: Antibodies deposited on fixed tissues activate complement ( $C1, C5a, C3b$ ). $C5a$ attracts neutrophils, which adhere to tissue via $Fc\gamma$ and $C3b$ receptors and release lysosomal enzymes and reactive oxygen species (ROS).
4. Antibody-Dependent Cellular Cytotoxicity (ADCC): Natural Killer (NK) cells bind antibody-coated target cells via Fc receptors ( $FcR$ ) and release perforin and granzymes or engage Fas/FasL, inducing target cell apoptosis.
5. Target Cell Malfunction: Anti-receptor antibodies bind cell surface receptors, inhibiting or inappropriately stimulating function without causing cell destruction (e.g., autoantibodies blocking acetylcholine receptors at the neuromuscular junction in Myasthenia Gravis).

Phagocytosis Mechanism in Type II Hypersensitivity

Type III Hypersensitivity: Immune Complex-Mediated Reactions

Mechanism: Caused by the formation of soluble antigen-antibody (immune) complexes in the circulation, which are subsequently deposited in vessel walls or extravascular tissues.
Pathogenesis:
- Reactions are not organ-specific.
- Tissue injury results from complement activation and subsequent neutrophil attraction; neutrophils attempt phagocytosis of deposited complexes and release toxic lysosomal enzymes.
Immune Complex Clearance Dynamics:
- Large Complexes: Cleared rapidly by tissue macrophages.
- Small Complexes: Filtered through the kidneys and excreted without causing local injury.
- Intermediate Complexes: Pathogenic; escape macrophage phagocytosis and renal filtration, depositing in tissue membranes (e.g., renal glomeruli, synovial membranes, blood vessel walls).
Clinical Forms:
- Serum Sickness: Systemic immune complex deposition affecting blood vessels, joints, and kidneys; clinically exemplified by Raynaud phenomenon.
- Arthus Reaction: Localized Type III response resulting from local antigen exposure in a previously sensitized individual. Features increased capillary permeability, neutrophil accumulation, localized edema, hemorrhage, microvascular clotting, and tissue necrosis within $1\text{--}2\text{ hours}$ .

Type IV Hypersensitivity: Cell-Mediated Reactions

Mechanism: Mediated directly by sensitized T lymphocytes without primary involvement of antibodies (delayed hypersensitivity).
Effector Mechanisms:
- Cytotoxic T Cells ( $T_c$ / CD8+): Recognize target antigens bound to MHC Class I molecules and cause direct cellular killing via perforin, granzymes, and Fas/FasL-mediated apoptosis.
- Helper T Cells ( $T_h1$ and $T_h17$ / CD4+): Recognize antigens bound to MHC Class II molecules and secrete cytokines (e.g., Interferon-gamma, $IFN-\gamma$ ) that activate and recruit macrophages, which damage tissue via lysosomal enzymes and reactive oxygen species.
Clinical Examples: Acute allograft rejection, tuberculin (TB) purified protein derivative (PPD) skin tests, allergic contact dermatitis, and autoimmune conditions such as Type 1 Diabetes Mellitus, Multiple Sclerosis, and Rheumatoid Arthritis.

Comparison Matrix of Hypersensitivity Types

Clinical Manifestations and Targets of Hypersensitivity

Allergens: Common environmental antigens include pollens, molds, fungi, foods (milk, eggs, shellfish, peanuts), animal dander/hair/saliva, insect stings, drugs, cigarette smoke, and house dust mites.
Atopy: A genetic predisposition to develop Type I IgE-mediated hypersensitivity reactions.
Clinical Manifestations of Allergy:
- Ocular/Nasal: Conjunctivitis, rhinitis.
- Respiratory: Bronchospasm, asthma, laryngeal edema.
- Cutaneous: Urticaria (hives), angioedema, eczema.
- Gastrointestinal: Nausea, vomiting, abdominal cramps, diarrhea, malabsorption.
Diagnostic Testing:
- Food challenge trials.
- Skin prick and patch testing.
- Laboratory assays measuring total and allergen-specific IgE.
Desensitization Therapy: Administration of gradually increasing doses of specific allergen to stimulate production of IgG "blocking antibodies" that clear the antigen before it can cross-link IgE on mast cells.
Hapten-Mediated Reactions:
- Contact Dermatitis (Type IV): Low-molecular-weight chemicals (haptens, e.g., poison ivy urushiol) bind host self-proteins in the skin to form immunogenic complexes.
- Drug Allergies (Types II and III): Drugs act as haptens, binding red blood cell or cell membrane surfaces to elicit IgG or IgM antibody responses.

Autoimmunity and Specific Autoimmune Disorders

Definition: Breakdown of immunological self-tolerance, causing the body's adaptive immune system to attack self-antigens.
Etiologic Mechanisms:
- Sequestered Antigens: Release of antigens normally hidden behind immune-privileged barriers (e.g., blood-brain or blood-testis barriers).
- Molecular Mimicry: Structural cross-reactivity between pathogens and self-antigens.
- Neoantigens: Alteration of self-proteins by chemical, physical, or hapten exposure.
- Survival of Forbidden Clones: Autoreactive lymphocytes that escape central clonal deletion in the thymus or bone marrow.
- Defective Peripheral Tolerance: Impairment in regulatory T cell ( $T_{reg}$ ) function.
- Genetic Factors: Strong familial aggregation associated with specific Human Leukocyte Antigen (HLA) alleles.
Systemic Lupus Erythematosus (SLE):
- A chronic, progressive multisystem autoimmune inflammatory disease.
- Pathophysiology: Production of autoantibodies against nucleic acids (anti-dsDNA, anti-Sm), erythrocytes, leukocytes, platelets, coagulation proteins, and phospholipids. Circulating DNA-anti-DNA immune complexes deposit in tissues throughout the body.
- Demographics: High female-to-male ratio.
- Clinical Manifestations: Arthralgias or nonerosive arthritis, vasculitis, facial (malar/butterfly) rash, discoid lesions, renal disease (lupus nephritis), hematologic cytopenias (anemia), and serositis.
- Diagnostic Criteria: Requires the presence of at least 4 of 11 classical findings:
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral or nasopharyngeal ulcers
5. Nonerosive arthritis (involving $\ge 2$ peripheral joints)
6. Serositis (pleuritis or pericarditis)
7. Renal disorders (proteinuria or cellular casts)
8. Neurologic disorders (seizures or psychosis)
9. Hematologic disorders (hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia)
10. Immunologic disorders (anti-dsDNA, anti-Sm, or anti-phospholipid antibodies)
11. Antinuclear antibodies (ANA) positive titer
- Pharmacotherapy: NSAIDs, systemic corticosteroids, antimalarial agents (e.g., hydroxychloroquine), intravenous immunoglobulin (IVIg), and immunosuppressive drugs.

Alloimmunity, Transfusion Reactions, and Transplant Rejection

Definition: Immune response targeting non-self tissue antigens from another individual of the same species.
Transient Neonatal Alloimmunity: Maternal IgG autoantibodies or alloantibodies cross the placenta, targeting fetal paternal antigens that the mother lacks.
ABO Blood Group System:
- Controlled by codominant carbohydrate antigens (A and B).
- Isohemagglutinins (naturally occurring IgM antibodies) develop against missing A or B antigens due to exposure to cross-reactive antigens on gut bacteria.
- Universal Recipient: Type AB (expresses both A and B antigens; lacks anti-A and anti-B antibodies).
- Universal Donor: Type O (lacks A and B antigens; contains anti-A and anti-B antibodies).

Rh Blood Group System:
- Expressed on red blood cells; presence of the D antigen defines Rh-positive status ( $Rh+$ ).
- Approximately $15\%$ of North American white individuals are Rh-negative ( $Rh-$ ).
- Exposure of $Rh-$ individuals to $Rh+$ blood induces anti-D IgG production.
- Hemolytic Disease of the Newborn (HDN): $Rh-$ mother sensitized to an $Rh+$ fetus during prior pregnancy transfers anti-D IgG across the placenta in subsequent $Rh+$ pregnancies, causing fetal erythrocyte destruction.
- Autoimmune Hemolytic Anemias:
- Warm Autoimmune Hemolytic Anemia: IgG autoantibodies bind red blood cells optimally at normal body temperature ( $37^\circ\text{C}$ ).
- Cold Autoimmune Hemolytic Anemia: IgM autoantibodies bind red blood cells in cooler peripheral regions of the body.
Transplant (Graft) Rejection:
- Driven by donor-recipient mismatches in Human Leukocyte Antigens (HLA); matching at the HLA-DR locus is most critical.
- Hyperacute Rejection: Immediate, rare thrombosis and graft necrosis caused by pre-existing recipient antibodies against donor tissue.
- Acute Rejection: Cell-mediated response occurring days to weeks post-transplant, driven by T cells targeting unmatched HLA antigens.
- Chronic Rejection: Progressive graft failure occurring over months or years, caused by low-grade cell-mediated and humoral responses against minor histocompatibility antigens.

Primary (Congenital) Immunodeficiencies

Etiology: Genetic defects, primarily single-gene mutations affecting components of the immune system.

Distribution of Primary Immunodeficiencies

Proportional Distribution of Primary Immunodeficiencies:
- Antibody Deficiencies: $65\%$
- Combined Cellular and Antibody Deficiencies: $15\%$
- Phagocytic Cell Deficiencies: $10\%$
- Cellular Deficiencies: $5\%$
- Complement Deficiencies: $5\%$
Severe Combined Immunodeficiencies (SCID):
- Characterized by complete absence of T-cell function along with severe (partial or complete) loss of B-cell function.
- Subtypes and Causes:
- Reticular Dysgenesis: The most severe form of SCID; failure of hematopoietic stem cell development in bone marrow.
- Adenosine Deaminase (ADA) Deficiency: Enzyme defect causing toxic purine metabolite accumulation in lymphocytes.
- X-Linked SCID: Defect in the common gamma chain of the Interleukin-2 ( $IL-2$ ) receptor.
- Janus Kinase 3 (JAK3) Deficiency: Impairs downstream signal transduction from cytokine receptors.
- $IL-7$ Receptor Deficiency: Prevents T-cell maturation in the thymus.
- Purine Nucleoside Phosphorylase (PNP) Deficiency: Purine metabolic defect, less severe than ADA deficiency.
- RAG-1 / RAG-2 Deficiency: Autosomal recessive mutations in Recombination Activating Genes preventing T-cell and B-cell receptor rearrangement.
- Bare Lymphocyte Syndrome: Inability to express MHC Class I or MHC Class II molecules (MHC Class II deficiency is clinically more severe).
Combined Deficiencies with Nonimmunologic Features:
- Wiskott-Aldrich Syndrome (WAS): X-linked recessive disorder; features low IgM, normal/high IgA and IgG, eczema, and thrombocytopenia.
- Ataxia-Telangiectasia (AT): Autosomal recessive defect in the $ATM$ gene impairing DNA repair.
- DiGeorge Syndrome: Partial or complete microdeletion of chromosome 22q11.2, leading to thymic hypoplasia or aplasia and absent T-cell immunity.
Predominantly Antibody Deficiencies:
- Bruton X-Linked Agammaglobulinemia: Mutation in Bruton tyrosine kinase ( $BTK$ ) blocking pre-B-cell maturation.
- Autosomal Agammaglobulinemia: Mutations in IgM heavy chain components.
- X-Linked Hyper-IgM Syndrome: Defective CD40 ligand on T cells preventing immunoglobulin class switching.
- Activation-Induced Cytidine Deaminase (AICD) Deficiency: Defective class-switch recombination at the DNA level.
- IgG Subclass Deficiency: Recurrent sinopulmonary infections (e.g., pneumonia).
- Selective IgA Deficiency: Complete absence of IgA; most common overall primary immunodeficiency.
- Common Variable Immunodeficiency (CVID): Most common severe, symptomatic primary immunodeficiency; features variable hypogammaglobulinemia.
Phagocyte Defects:
- Severe Congenital Neutropenia (and milder Cyclic Neutropenia): Severe susceptibility to bacterial infections.
- Leukocyte Adhesion Deficiency (LAD-1, LAD-2): Integrin/selectin mutations preventing phagocyte extravasation into inflamed tissues.
- Chronic Granulomatous Disease (CGD): NADPH oxidase complex mutations impairing the oxidative burst and bacterial killing.
- Myeloperoxidase (MPO) Deficiency: Complete or partial enzymatic loss of MPO.
Defects in Innate Immunity and Autoinflammatory Disorders:
- Chronic Mucocutaneous Candidiasis: Selective T-cell defect impairing responses against Candida albicans.
- Familial Mediterranean Fever: Common in Eastern Mediterranean populations; uncontrolled release of $IL-1\beta$ inflammasomes in granulocytes/monocytes, presenting with recurrent fever and leg rashes.
Complement Deficiencies:
- C3 Deficiency: Most severe complement deficiency; C3 is central to all activation pathways, and $C3b$ is a key opsonin.
- Mannose-Binding Lectin (MBL) Deficiency: Predisposes to fungal and yeast infections.
- Properdin Deficiency: X-linked defect causing high susceptibility to Neisseria meningitidis infections.
- Factor I and Factor H Deficiencies: Unregulated complement activation leading to secondary C3 depletion.
- C5 through C9 Deficiencies: Impair Membrane Attack Complex (MAC) formation; C9 deficiency is the most common; all predispose to recurrent Neisseria infections.

Secondary (Acquired) Immunodeficiencies

Prevalence: Far more common than primary (congenital) immunodeficiencies.
Etiologies: Non-genetic causes including physiological stress, malnutrition, aging, metabolic disease (e.g., Diabetes Mellitus), malignancy, chronic illnesses, environmental exposures, physical trauma, immunosuppressive medications/radiation, and viral infections (e.g., Human Immunodeficiency Virus / HIV).
Hallmark Clinical Presentation: Recurrent, severe, or atypical infections caused by opportunistic organisms.
Diagnostic Clues from Infection Type:
- Recurrent Neisseria / gonococcal infections: Suggest complement deficiencies.
- Severe viral or fungal infections: Suggest T-cell deficiencies.
- Infection with encapsulated bacteria requiring opsonization: Suggest B-cell or phagocyte defects.

Clinical Evaluation, Diagnostics, and Management of Immunodeficiencies

Diagnostic Evaluation:
- Complete Blood Count (CBC) with differential to evaluate leukocyte and lymphocyte subpopulations.
- Quantitative Immunoglobulin Assays (measuring IgG, IgA, IgM levels).
- Assay for Total Complement Activity ( $CH_{50}$ ).
- Delayed-type hypersensitivity skin testing (evaluating functional cell-mediated immunity).
Replacement and Therapeutic Interventions:
- Gamma-Globulin Therapy: Intravenous (IVIg) or intramuscular (IMIg) passive antibody administration; duration of action is $3\text{--}4\text{ weeks}$ .
- Transplantation: Hematopoietic stem cell or bone marrow transplantation requiring strict HLA matching.
- Soluble Immune Modulators: Cytokine replacement to boost T-cell function.
- Gene Therapy: Insertion of functional functional genes into target stem cells.
Clinical Precautions in Immunocompromised Patients:
- Avoid Live Attenuated Vaccines: Risk of vaccine-induced infection.
- Graft-versus-Host Disease (GVHD): Transfused mature donor T cells attack immunocompromised host tissues; prevented by irradiating blood products prior to administration.