Immunity

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Definitions
Types: Innate Immunity (Natural Immunity)
Types: Adaptive Immunity
Pathophysiology: Inadequate Host Immune Response
Pathophysiology: Exaggerated Host Immune Response
Prevention
Resources
References
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II. Definitions

Immune System
1. Defense mechanism against both errant native cells and foreign organism or substance invasion
  1. Distinguishes self from non-self
  2. Eliminates foreign organisms and substances
2. Responses include humoral immune response and the cell-mediated response
  1. Organs (Thymus, Spleen, Tonsils, Lymphatic System, hematopoetic system)
  2. Cells (Lymphocytes, Granulocytes, Monocytes, Macrophages)
  3. Molecules (antibodies, complement, Cytokines)
Innate Immunity (Natural Immunity)
1. Generalized, immediate immune response not reliant on prior exposure
2. Predates the evolution of the more specific Immunity provided by antibodies and Lymphocytes
Adaptive Immunity
1. Organism specific Immunity that relies on prior "memory" of exposure
2. Immune System evolved beyond the more primitive Innate Immunity
  1. Humoral Immunity (Antibody and B Cell response)
  2. Cell mediated Immunity (T Cell Response)
Phagocyte (and Phagosome, Phagocytosis)
1. Immune cells (Neutrophils and Monocytes/Macrophages) are White Blood Cells that engulf pathogens and foreign material
2. Phagosomes are the membrane engulfed pathogens
3. Often combined with lysis by Lysozymes
Lysosome (and Lysozyme)
1. Lysozyme-containing vacuoles produced in cellular golgi apparatus
2. Lysomsomes fuse with Phagosomes, resulting in pathogen lysis (esp. Bacterial cell walls)
3. Lysosomes, like Phagosomes, are found in Phagocytes (Macrophages and Neutrophils)
Opsonin (and Opsonization)
1. Proteins (e.g. Antibody, complement, C-Reactive Protein) that bind a pathogen surface, targeting it for Phagocytosis

III. Types: Innate Immunity (Natural Immunity)

Physical Barriers
1. Skin
2. Mucosa (e.g. respiratory and Gastrointestinal Tract)
3. Cilia (e.g. respiratory)
Inflammatory Response
1. C-Reactive Protein
  1. Increases with inflammation and tissue injury
  2. Binds Bacterial surface and facilitates Phagocytosis (by Macrophages and Neutrophils)
2. Prostaglandins and Leukotrienes
  1. Fatty Acids released from injured cells, as well as Mast Cells
  2. Promote inflammation (e.g. vascular permeability, Neutrophil chemotaxis, stimulate Nociceptors)
3. Kinin peptides (kallidin and bradykinin)
  1. Short-lived inflammatory Proteins that increase vascular permeability and result in arteriolar dilitation
4. Cytokines
  1. Cytokine types include Interleukin, Interferon, Tumor Necrosis Factor, Colony-Stimulating Factor, TGF-beta
  2. Glycoproteins act in inflammatory and immune response via cell to cell communication
  3. Released from cells in response to a trigger (e.g. Antigen binding) and bind and activate Target Cells
Secretion Contents
1. Lysozyme (e.g. in tears, Saliva and in Neutrophils)
  1. Enzymatically degrades cell walls
2. Acid destroys acid-labile organisms
  1. Sweat Lactic Acid
  2. Stomach Gastric Acid (Hydrochloric Acid)
Phagosomes (Phagocytosis)
1. Phagocytes such as Neutrophils (PMNs) and Macrophages attract and engulf organisms (Phagocytosis)
2. Phagocytes attract organisms which in turn activate Phagocytosis
3. Phagosomes are later lysed via Lysosomes (as below)
Lysosomes
1. Neutrophil's and Macrophage's (Phagocytes) golgi apparatus produce Lysosomes (vacuoles) that contain Lysozyme
2. Lysosomes fuse with Phagosomes to produce phagolysosomes, degrading the engulfed organisms
3. Lysosomes may also release their contents extracellularly to lyse larger targets too large to engulf
Spleen responds to blood borne pathogens
1. Red Pulp
  1. Vascular Sinusoids at the end of arterioles
  2. Filter blood of Red Blood Cells and non-immunogenic foreign material
2. White Pulp
  1. Collections of Macrophages, plasma cells, dentritic cells and Lymphocytes
Natural Killer Cells (NK cells)
1. Lymphocytes providing protection against Intracellular Bacteria and viruses
2. NK cells bind Major Histocompatibility Complex 1 (MHC-1)
  1. MHC-1 is present on normal cells and it inactivates NK cells
  2. MHC-1 is NOT expressed by infected cells
    1. NK activating receptor Ligand is expressed
    2. NK cells bind infected cells and destroy them
3. NK cell mechanisms of infected cell destruction
  1. Cytoplasmic granules
    1. Perforin
      1. Generates pores on cells targeted for destruction
    2. Granzyme
      1. Induces programmed cell death (apoptosis) on entry into Target Cells
  2. Cytokines
    1. Interferon-Gamma (IFN-g)
      1. Activates Macrophages for Phagocytosis
4. Image: NKC Mediated Destruction of Infected Host Cells
Complement Pathway
1. Images
2. Activation
  1. Classical Pathway (C1, C2, C3, C4)
    1. C1 binds Antigen-Antibody complex
  2. Alternate Pathway (Properdin, Factor B, Factor D, C3)
    1. Activation via Microbe cell surface
  3. Lectin Pathway (Mannose Binding Lectin or MBL)
    1. Mannose Binding Lectin (MBL) binds mannose on Microbe surface
    2. Mannose Binding Lectin Associated Proteases (MASP-1, MASP-2) are activated
    3. Classical Pathway (above) is stimulated
3. Enzyme C3 Convertase (C3bBb or C4b2a) Formation
  1. Enzyme C3 Convertase splits C3 into C3a and C3b
  2. C3a stimulates inflammation (attracts Neutrophils, Histamine release)
  3. C3b stimulates Phagocytosis, inflammation (as with C3) and lysis (see below)
4. Opsonization
  1. Microbe coated with an Opsonin, an Antibody or complement (e.g. C3b)
  2. Surface Opsonins target Microbes for Phagocytosis
5. Phagocytosis
  1. Phagocytes such as Neutrophils (PMNs) and Macrophages attract and engulf targeted organisms
6. Inflammation (via C3a, C5a)
  1. Chemoattraction of Neutrophils
  2. Anaphylatoxic activation of Mast Cells and Basophils to degranulate, releasing Histamines and vasoactives
    1. Inflammation occurs when Histamine-induced capillary dilation results in fluid and Protein release
7. Lysis
  1. C3b splits C5 into C5a and C5b
  2. Membrane attack complex or MAC (C5b, C6, C7, C8, C9) binds Microbe surface
  3. MAC promotes Microbe lysis by creating holes in Microbe surface, resulting in leak

IV. Types: Adaptive Immunity

Humoral Immunity (B-Cells and Antibodies)
1. Humoral Immunity (i.e. antibodies) targets extracellular pathogens
2. B Cells
  1. Derivation
    1. Fetal Liver
    2. Bone Marrow Pluripotent Stem Cells
  2. Peripheral Migration to Secondary Lymphoid Tissue
    1. Spleen
    2. Lymph Nodes
    3. Peyer's Patches (Small Bowel)
  3. Activation
    1. Images
    2. Recognition
      1. Antigen binds B-Lymphocyte Surface Receptor (BCR)
      2. BCR binding activates B-Lymphocyte
        T-Cell Independent Antigen (e.g. inert Antigens) alone activate B-Cells
        T-Cell Dependent Antigen (e.g. Microbes) require added stmulus (e.g. T Cells)
    3. B-Cell Proliferation
      1. Activated Lymphocytes proliferate
    4. B-Cell Differentiation
      1. Plasma Cells (Antibody producing cells)
        Survive for days to weeks producing antibodies, and without replicating
      2. Memory Cells
        Remain in B-Lymphocyte pool ready to respond to the same Antigen in future
        Future Antigen response is known as secondary immune response
3. Antibodies
  1. Images
  2. Immunoglobulin (Ig)
    1. Immunoglobulins (or antibodies) are Y-Shaped Glycoproteins generated by Plasma Cells
    2. Immunoglobulin stem (Fc) is composed of 2 identical heavy chains
    3. Two Immunoglobulin Arms emanate from the stem
      1. Each arm is composed of 2 heavy chains and 2 light chains
      2. The end of each arm contains an Antigen binding site (Fab)
    4. Immunoglobulins have 2 forms
      1. Membrane bound Immunoglobulins (on surface of B-Cell)
      2. Secretory Immunoglobulin (unbound, free-floating)
        Monomeric antibodies exist as single Antibody molecules (IgE or IgG)
        Multimeric antibodies exist as multiple joined antibodies (IgA or IgM)
        Connected with J Chains
  3. Immunoglobulin G (IgG and subclasses IgG1-4)
    1. Monomer accounting for 75% of all Antibody, and has a serum Half-Life of 23 days
    2. Responsible for long lasting Immunity (secondary immune response) and Type 2 Hypersensitivity
  4. Immunoglobulin A (IgA and subclasses IgA1, IgA2)
    1. Dimer (2 Antibody molecules) when secretory Ig and accounts for 10-15% of all Antibody
    2. Serum half life of 6 days
    3. Present in body secretions (e.g. tears, Saliva, milk) and responsible for mucosal Immunity
  5. Immunoglobulin M (IgM)
    1. Pentamer (5 Antibody molecules) when secretory Ig
    2. Responsible for early, primary Antibody response
  6. Immunoglobulin E (IgE)
    1. Long stem (Fc) monomeric Antibody with serum Half-Life of only 2.5 days
    2. Reacts to allergans (Type 1 Hypersensitivity) and Parasitic Infections
  7. Immunoglobulin D (IgD)
    1. Monomer with serum half life of 3 days
    2. Membrane bound surface Antibody
Cell-Mediated Immunity (T-Cells)
1. Cellular Immunity (i.e. T Cells) target Intracellular Pathogens (e.g. viruses and Intracellular Bacteria)
2. T-Cells
  1. Derived in Bone Marrow
  2. Migrate to Thymus
    1. Maturation and Differentiation into two cell lines with different T-Cell Receptors (CD4 and CD8)
  3. Release into peripheral circulation
3. T-Cell Surface Receptors
  1. T-Cell Receptors (TCR)
    1. Bind the Antigen on the Antigen Presenting Cell
    2. TCR Types
      1. TCR-alpha-beta (TCRab+)
      2. TCR gamma-delta (TCRgd+)
  2. T-Cell Co-Receptors
    1. CD4 binds MHC Class 2 - peptide/Antigen complex on surface of Antigen Presenting Cells (APC)
      1. Only Dendritic Cells, Macrophages, B-Cells (B-Lymphocyte) present MHC Class 2
    2. CD8 binds MHC Class 1 - peptide/Antigen complex on surface of Antigen Presenting Cells (APC)
      1. Any nucleated cell can present MHC Class 1
4. T-Cell Types
  1. Effector Cells
    1. T-Helper Cells (CD4+ Cells)
      1. Releases Interferon
        Stimulates Phagocytosis by Macrophages
        Activates Natural Killer Cells
        Suppresses viral replication
      2. Releases interleuken 2
        Promotes T-Cell proliferation (esp. memory cells)
        Promotes B-Cell proliferation (memory cells and plasma cells)
    2. T-Cytotoxic Cells (CD8+ Cells)
      1. Target and destroy tumor cells and virus-infected cells
  2. Other Cells
    1. Memory Cells
    2. Apoptosis of some cells not otherwise differentiated
5. Naive T-Cell Activation
  2. T-Cell Receptor (TCR) binds to MHC-Antigen complex on Antigen Presenting Cells
  3. T-Cell Surface CD28 binds to B7 Ligand on Antigen Presenting Cell
  4. T-Cell Surface LFA-1 (Lymphocyte Function Associated Antigen) binds ICAM1 on Antigen Presenting Cells
  5. Interleukin-2 (IL2) produced by naive T Cells
    1. Stimulate T Cell proliferation

V. Pathophysiology: Inadequate Host Immune Response

Infections
1. See Bacterial Infection and Sepsis
2. See Viral Infection
3. See Parasitic Infection
4. See Cutaneous Fungal Infection, Fungal Lung Infection, Candida Vulvovaginitis and Oral Candidiasis
5. See Prion Disease
6. Microorganisms adapt to host immune response
  1. Microorganisms may vary their Antigens or only trigger a weak Antigen immune response
  2. Bacterial encapsulation prevents Phagocytosis by Macrophages
  3. Bacterial cell wall may be resistant to immune-mediated lysis
  4. Bacteria may release toxins to counter or degrade host defenses
    1. Endotoxins (esp. Gram Negative Bacteria)
    2. Exotoxins (may damage Macrophages)
    3. Aggressins (increase Bacterial virulence, penetration, spread and persistence)
Immunodeficiency
1. Primary Immunodeficiency
  1. Rare immune disorders of childhood
  2. Genetic abnormalities affecting T-Cells, B-Cells, Phagocytes or Complement
    1. Humoral Immunodeficiency (B-Cell Disorder, Immunoglobulin Disorder, Antibody Disorder)
    2. Cell-Mediated Immunodeficiency (T-Cell Disorder, e.g. DeGeorge Syndrome)
    3. Phagocytic Immunodeficiency
    4. Complement Disorders
2. Secondary Immunodeficiency (Acquired Immunodeficiency)
  1. Asplenism (e.g. splenectomy, Sickle Cell Anemia)
  2. Immunosuppressants
  3. Malnutrition
  4. Cancer involving Bone Marrow
  5. Radiation Therapy
  6. HIV Infection or AIDS (T Helper cell or CD4+ Cell infection)

VI. Pathophysiology: Exaggerated Host Immune Response

Non-Hypersensitivity Reactions
1. Schwartzman Reaction
  1. Excess Tumor Necrosis Factor induced by Bacterial endotoxins resulting in shock state, DIC
2. Excess Complement Activation (confirmed or proposed as mechanism in wide variety of conditions)
  1. Resistant infectious disease
  2. Hereditary Angioneurotic Edema
  3. Paroxysmal Nocturnal Hematuria
  4. Alzheimer's Disease
  5. Schizophrenia
  6. Atypical Hemolytic-Uremic Syndrome
  7. Macular Degeneration
  8. Crohn's Disease
  9. Tichaczek-Goska (2012) Adv Clin Exp Med 21(1):105-14 +PMID: 23214307 [PubMed]
3. Cytokine Release Syndrome
  1. Sepsis-like systemic inflammatory reaction due to excessive systemic release of Cytokines by activated T-Cells
  2. Infections
    1. Corona Virus 19
    2. Bubonic Plague
    3. Pandemic Influenza 1918
    4. Toxic Shock Syndrome
  3. Acute Graft Versus Host Disease
    1. Allogeneic Graft with Hematopoietic Stem Cell Transplant
  4. Chemotherapy
    1. Muromonab-CD3 (OKT3) Infusion
    2. Chimeric Antigen Receptor T Cell Therapy (CAR T-Cell Therapy)
4. Other Conditions with Exaggerated Host Response
  1. Acute Respiratory Distress Syndrome (ARDS)
  2. Tumor Lysis Syndrome
  3. Hemophagocytic Lymphohistiocytosis (HLH)
  4. Macrophage activation syndrome (MAS)
Hypersensitivity Reaction (Gell and Coombs Classification, including autoimmune reactions)
1. Type 1 - Immediate Hypersensitivity Reaction (IgE Antibody mediated)
  1. Immediate allergan immune response after repeated exposure (esp. in Atopic Patients)
  2. Examples
    1. Anaphylaxis (e.g. Penicillin)
    2. Urticaria
    3. Angioedema
    4. Anaphylactoid Reaction (e.g. Anaphylactoid Reaction to Radiocontrast)
    5. Atopic Allergy (e.g. Allergic Rhinitis, Allergic Asthma)
    6. Food Allergy
    7. Bee sting Allergy
    8. Allergic Occupational Asthma
2. Type 2 - Cytotoxic Antibody Reaction (non-IgE Antibody Mediated Reaction)
  1. See Autoimmunity
  2. Mediated by IgG and IgM (on cell surface or extracellular complex) to specific Antigens
  3. Antibody-Antigen Complex destruction (Phagocytosis, Antibody cellular cytotoxicity or complement)
  4. Examples
    1. Transfusion Reaction (ABO Incompatibility)
    2. Rhesus Incompatibility (Rh Incompatibility, Autoimmune Hemolytic Anemia)
    3. Autoimmune Thrombocytic Purpura
    4. Hashimoto's Thyroiditis
    5. Grave's Disease
    6. Goodpasture's Syndrome
    7. Delayed transplant Graft Rejection
    8. Myasthenia Gravis
    9. Mycoplasma pneumoniae related cold Agglutinins
    10. Polyclonal Activation (triggered by Microorganism response, e.g. Trypanosoma cruzi)
      1. Montes (2007) J Leukoc Biol 82(5):1027-32 +PMID: 17615380 [PubMed]
3. Type 3 - Immune Complex Reaction
  1. Antigen-Antibody immune complexes deposit in tissue (small complexes missed by Phagocytosis)
  2. Site of immune complex deposition determines effects (e.g. Vasculitis, nephritis, Arthritis)
  3. Examples
    1. Serum Sickness (prototypical Immune Complex Reaction)
    2. Systemic Lupus Erythematosus
    3. Erythema Nodosum
    4. Polyarteritis Nodosa
    5. Arthus Reaction (e.g. Farmer's Lung)
    6. Rheumatoid Arthritis
    7. Elephantiasis (Wuchereria bancrofti reaction)
    8. Jarisch-Herxheimer Reaction
4. Type 4 - Delayed-Type Hypersensitivity (Cell-Mediated)
  1. Reaction within 2-7 days after exposure
  2. Mediated by Effector T Lymphocytes (CD4+ and CD8+), activated in response to specific Antigens
  3. Examples
    1. Allergic Contact Dermatitis (e.g. Nickel allergy)
    2. Mantoux Test (PPD)
    3. Immune Allergic Contact Dermatitis after prior Mycobacterium tuberculosis exposure

VII. Prevention

VIII. Resources

Immune System (Wikipedia)
1. https://en.wikipedia.org/wiki/Immune_system

IX. References

Goldberg (2014) Physiology, MedMaster, Miami, FL
Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL
Guyton and Hall (2006) Medical Physiology, p. 419-50

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