Immunopathology Notes

Immune Response

• A well-developed system of organs, tissues, cells, and molecules interacting to maintain homeostasis.
• Mediated by cells and proteins always ready to react against infectious pathogens.
• Normally silent, responds by neutralizing and eliminating pathogens.

Innate Immunity

• Nonspecific defense system present at birth.
• First immunological defense.

Major Components

• Epithelial barriers
• Phagocytic cells (neutrophils, macrophages)
• Dendritic cells
• Natural killer (NK) cells
• Plasma proteins

Pathogen-Associated Molecular Patterns (PAMPs)

• Recognized by Pattern Recognition Receptors (PRRs).
• Examples include:
  • TLR2 recognizing lipopeptides.
  • TLR5 recognizing flagellin.

Major Classes of Innate Immune Receptors

• Toll-like receptors (TLRs)
• NOD-like receptors (NLRs) in the cytosol
• C-type lectin receptors
• RIG-like receptors for viral RNA
• Cytosolic DNA sensors

Reactions of Innate Immunity

• Inflammation: Cytokines and complement products trigger vascular and cellular inflammation.
  • Recruited leukocytes destroy pathogens and eliminate damaged cells.
• Anti-viral defense: Type I interferons activate enzymes that degrade viral nucleic acids and inhibit viral replication.
• The innate immune system stimulates the adaptive immune response.

Adaptive Immunity

• Consists of lymphocytes and their products (antibodies).
• Recognizes a vast array of foreign substances.

Types of Adaptive Immunity

• Humoral Immunity:
  • Effective against extracellular microbes.
  • Mediated by B lymphocytes.
  • Antibodies block infections and eliminate microbes.
• Cell-Mediated Immunity:
  • Effective against phagocytosed microbes in macrophages and intracellular microbes.
  • Mediated by T lymphocytes.
  • Helper T lymphocytes activate macrophages.
  • Cytotoxic T lymphocytes kill infected cells.

Acquired Immunity

• Immunity developed during life.
• Active Immunity:
  • Develops after exposure to an infection or vaccination.
  • Natural: Antibodies made after exposure.
  • Artificial: Antibodies made after vaccination.
• Passive Immunity:
  • Acquired from someone else.
  • Natural: Antibodies from mother to baby (e.g., breast milk).
  • Artificial: Antibodies from immune serum medicine.

Cells and Tissues of the Immune System

• Stem cells in the red bone marrow differentiate into:
  • Pre-B cells that become B cells.
  • Pre-T cells that migrate to the thymus and become T cells.
• B and T cells circulate through the blood and lymph nodes.

Lymphoid Organs

• Central Lymphoid Organs (Primary):
  • Thymus
  • Bone Marrow
• Secondary Lymphoid Organs:
  • Lymph nodes
  • Spleen
• Secondary Lymphoid Organs Associated with Mucosa:
  • Waldeyer’s Ring
  • Peyer’s patches
  • Non-encapsulated lymphoid tissue

Macrophages

• Tissue-specific macrophages:
  • Spleen: White-pulp, Red-pulp, Marginal-zone, Metallophilic macrophages.
  • Bone: Osteoblasts.
  • CNS: Microglial cells.
  • Lung: Alveolar macrophages.
  • Liver: Kupffer cells.
  • Connective tissue: Histiocytes.

Dendritic Cells

• Antigen-presenting cells (APCs) that capture, process, and present antigens to lymphocytes.
• Initiate and regulate the adaptive immune response.
• Heterogeneous population found in skin, mucosa, submucosa, lymph nodes, and interstitial layers.
• Originate from a specialized monocyte lineage.

T Lymphocytes

• Derived from BM stem cells; mature in the thymus.
• Constitute 60-70% of blood lymphocytes; found in T cell zones.
• Recognize peptides presented by MHC of antigen-presenting cells.
• Express receptors for chemokines.
• Recognize specific cell-bound antigens via T cell receptor (TCR).
• Require antigen presentation; cannot be activated by soluble antigens.

Types of T Cells

• Naïve T cell: Has not encountered an antigen.
• Regulatory T cell: Modulates the immune system, prevents autoimmune disease.
• Memory T cell: Augmented immune response upon reintroduction of a pathogen.
• CD4+ T helper cell: Assists other lymphocytes to mature and activate.
• CD8+ T-killer cell: Destroys virus-infected cells and tumor cells.

B Lymphocytes

• Derived from BM precursors; constitute 10-20% of blood lymphocytes.
• Recognize antigens through B-cell antigen receptor complex (IgM & IgD).
• Form plasma cells that secrete Igs.
• Require help from CD4+ T cells; stimulated by antigens and other signals.

Natural Killer Cells

• Large granular lymphocytes that constitute 10-15% of blood lymphocytes.
• Possess innate ability to kill without prior sensitization to antigens.
• Target tumor cells, virally infected cells, and some normal cells.
• Secrete cytokines (e.g., IFN-gamma).
• Recognize antigen combined with class 1 MHC.

Principal Classes of Lymphocytes and Their Functions

• T lymphocytes:
  • Helper T lymphocytes: Activation of macrophages, inflammation, activation of T and B lymphocytes
  • Cytotoxic T lymphocytes: Killing of infected cells.
  • Regulatory T lymphocytes: Suppression of immune response.
• B lymphocytes:
  • Antibody production: Neutralization of microbe, phagocytosis, complement activation.
• Natural killer cells:
  • Killing of infected cells.

Hypersensitivity

• Immunologically mediated tissue injury.

Causes of Hypersensitivity Reactions

• Autoimmunity: Reactions against self antigens (autoimmune diseases).
• Reactions against microbes.
• Reactions against environmental antigens.

Types of Hypersensitivity

• Type I. Immediate hypersensitivity (allergies).
• Type II. Antibody-mediated disorders.
• Type III. Immune complex–mediated disorders.
• Type IV. T cell–mediated disorders.

Type I: Immediate, IgE-Mediated

• Characterized by an immediate reaction in a sensitized individual, typically within minutes of exposure.
• Tendency to develop type I hypersensitivity is inherited.
• Reactions occur in 20-30% of the population.

Mechanism

• Sensitization: Antigen contact induces an IgE response.
• IgE antibodies bind to receptors on mast cells and basophils.
• Antigen binds to IgE on mast cells, causing degranulation and release of mediators (urticaria, hay fever, anaphylaxis).

Allergen Exposure:
* Mucosal dendritic cells capture allergen.
* Activation of TH2 cells and class switching in B cells, leading to IgE production.
* IgE binds to FceRI on mast cells.
* Repeat exposure to allergen leads to mast cell activation and mediator release.

Phases

• Immediate response: Stimulated by mast cell granule contents and lipid mediators.
  • Characterized by vasodilation, vascular leakage, and smooth muscle spasm.
  • Evident within 5-30 minutes, subsiding by 60 minutes.
• Late-phase reaction: Stimulated by cytokines, setting in 2-8 hours later, lasting for several days.
  • Characterized by inflammation, tissue destruction.
  • Dominant inflammatory cells are neutrophils, eosinophils, and lymphocytes (TH2 cells).

Microscopic Features

• Mast cells
• Edema
• Vascular congestion
• Eosinophils

Clinical Manifestations

• Local anaphylaxis:
  • Hives
  • Hay fever
  • Asthma
  • Respiratory allergy
• Generalized anaphylaxis:
  • Itching
  • Urticaria (hives)
  • Respiratory difficulty due to bronchoconstriction and mucus hypersecretion.
  • Laryngeal edema
  • Vomiting, abdominal cramps, diarrhea
  • Systemic vasodilation (anaphylactic shock)

Summary

• Immune Mechanisms: IgE production → vasoactive amine release from mast cells; recruitment of inflammatory cells.
• Histopathology: Vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation.
• Prototypical Disorders: Anaphylaxis, allergies, bronchial asthma.

Type II: Antibody-Mediated Disorders

• Caused by antibodies directed against target antigens on cell surfaces or tissues.
• Antigens can be normal molecules, or adsorbed exogenous antigens (e.g., drug metabolites).

Mechanisms

• Opsonization and phagocytosis: Antibodies and complement opsonize cells for phagocytosis.
• Complement- and Fc receptor-mediated inflammation: Complement byproducts recruit neutrophils, causing inflammation and tissue injury.
• Antibody-mediated cellular dysfunction: Antibodies inhibit or stimulate cell receptors.

Diseases

Summary

• Immune Mechanisms: IgG, IgM binds to antigen on target cell → phagocytosis or lysis of target cell; recruitment of leukocytes.
• Histopathology: Phagocytosis and lysis of cells; inflammation; functional derangements.
• Prototypical Disorders: Autoimmune hemolytic anemia; Goodpasture syndrome.

Type III: Immune Complex-Mediated Disorders

• Antigen-antibody complexes deposit in blood vessels, leading to complement activation and acute inflammation.
• Antigens may be exogenous or endogenous.

Diseases

Morphology

• Acute vasculitis: fibrinoid necrosis of the vessel wall and intense neutrophilic infiltration.

Summary

• Immune Mechanisms: Deposition of antigen-antibody complexes → complement activation → recruitment of leukocytes; release of enzymes.
• Histopathology: Inflammation, necrotizing vasculitis (fibrinoid necrosis).
• Prototypical Disorders: Systemic lupus erythematosus; some forms of glomerulonephritis; serum sickness; Arthus reaction.

Type IV: T Cell-Mediated Disorders

• Causes include autoimmune disorders, reactions to environmental chemicals, and persistent microbes.

Mechanisms

• Cytokine-mediated inflammation (CD4+ T cells).
• Direct cell cytotoxicity (CD8+ T cells).
• T cells are increasingly recognized as the basis of chronic inflammatory diseases.

Diseases

Summary

• Immune Mechanisms: Activated T lymphocytes → cytokine release, inflammation, macrophage activation; T cell-mediated cytotoxicity.
• Histopathology: Perivascular cellular infiltrates; edema; granuloma formation; cell destruction.
• Prototypical Disorders: Contact dermatitis; multiple sclerosis; type I diabetes; tuberculosis.