Therapeutics Rheumat Witt Flashcard

Rubor, Tumor, Calor, Dolor, Functio laesa

  • Redness
  • Swelling
  • Heat
  • Pain
  • Loss of function

The innate immune response involves:

  1. Phagocytic cells (neutrophils, monocytes, macrophages)
  2. Cells that release inflammatory mediators (basophils, mast cells, eosinophils)
  3. Natural killer cells
  4. Molecules such as complement proteins, acute phase proteins, cytokines

Four General Stages of Diapedesis

1.  Chemoattraction and Leukocyte activation

  • Macrophages release IL-1, IFN-α, and chemokines
  • IL-1 and IFN-α cause endothelial cells of blood vessels near the site of infection to express cellular adhesion molecules, including selectins
  • Circulating leukocytes are localized towards the site of injury or infection due to the presence of chemokines

2.  Rolling adhesion

  • Selectin ligands on circulating leukocytes bind selectins on the inner wall of the vessel
  • Histamine promotes the expression of P-selectin on endothelial cell surfaces — forms weak bonds between the endothelial cell and the leukocyte which causes it to “roll”
  • Cytokines induce the expression of E-selectin, which works in the same way as P-selectin
  • Cytokines also induce the expression of integrin ligands on endothelial cells, which further slow down leukocytes

3.  Tight adhesion

  • Chemokines released by macrophages causes integrin ligands to switch from low-affinity to high-affinity

4.  Transmigration

  • Reorganization of cytoskeleton of leukocytes –> leukocytes extend pseudopodia and pass through gaps between endothelial cells
  • PECAM proteins pull the cell in between the endothelium
  • Leukocytes secrete proteases that degrade the basement membrane, allowing them to escape the blood vessel

Natural Killer Cells

  • Part of the innate immune system
  • Defends host from tumors and virally infected cells
  • Targets cells that lack MHC
  • They also have Fc receptors and can kill cells by antibody-dependent cellular cytotoxicity

Natural Killer Cells are activated via:

  1. Cytokines (IFN-α/β/γ, IL-2, IL-12)
  2. Fc receptor (antibody-dependent cellular cytotoxicity)
  3. Activating receptors

Natural Killer Cells: Mechanism of Killing

1.  Perforins

  • forms pores in cell membranes of target cells for which the granzymes can enter

2.  Granzymes

  • Enters target cells through pores and induces apoptosis

Mast Cells

  • Has receptors for IgE and complement components C3a and C5a –> ligands acting at these receptors (as well as direct damage) trigger mediator release
  • Releases mainly histamine, as well as heparin, leukotrienes, PGD2, platelet-activating factor, nerve growth factor, and some interleukins
  • Binds to, ingests, and kills bacteria
  • Found alongside blood vessels in tissues

Platelets

  • Key factor in blood clotting and vascular spasm but also involved in inflammation
  • Generates thromboxane, platelet-activing factor, free radicals, proinflammatory cationic proteins, and platelet-derived growth factor
  • Platelet-derived growth factor contributes to the repair processes that follow inflammatory responses or damages to blood vessels

 

Complement System

  • Consists of a number of small proteins found in the blood, normally circulating as zymogens
  • When stimulated, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages
  • The end result is activation of the Membrane Attack Complex –> it forms a transmembrane channel, which causes osmotic lysis of the target cell
  • The complement system is not adaptable and does not change throughout a person’s lifetime — hence it is part of the innate immune system
  • During the process of opsonization, antigens are bound by antibody and/or complement molecules — phagocytic cells express receptors that bind opsonin molecules — with the antigen coated in these molecules, binding of the antigen to the phagocyte is greatly enhanced — targeted cell is destroyed by phagocyte

Acquired Immunity can be divided into two major phases

1.  Induction Phase

  • Antigen is presented to T-cell by large dendritic cells
  • This is followed by complex interactions of those T cells with B cells and other T cells
  • On first contact with an antigen, the lymphocytes that have ‘recogized’ it undergo clonal expansion, giving rise to a mass of cells that all have the capacity to recognize and respond to a particular pathogen

2.  Effector Phase

  • Lymphocytes differentiate into plasma cells or memory cells
  • Plasma cells produce antibodies (B-cell) or are involved in cell-mediated immune responses such as activating macrophages or killing virus-infected host cells (T-cell)
  • Can be further broken down into cell-mediated immunity and humoral mediated immunity

MHC I

  • Part of the induction phase
  • Interacts with CD8 Cytotoxic T-cells
  • Found on all nucleated cells

MHC II

  • Part of the induction phase
  • Interacts with CD4 T-Helper cells
  • Constitutively expressed in B lymphocytes, dendritic cells, thymic epithelial cells
  • Inducible expression in macrophages and endothelial cells

Antigen Presenting Cells

  • Presents foreign antigen complexed with MHC on its surface to undifferentiated T-cells
  • If antigen is recognized as foreign, the T-cell will become a Cytotoxic T-cell or Helper T-cell
  • Types of APCs:

1. Dendritic cells

2. Macrophages

3. B-cells

 

Stimulation of CD4 Cells

  • After stimulation by the APC, T-cells develop IL-2 receptors and secrete IL-2 in an autocrine fashion, resulting in a clone termed Th0 cell
  • The Th0 cell in turn gives rise to two different types of T-Helper cells

1.  Th1 Cells

  • Produce cytokines (IL-2, TNF-β, IFN-γ)
  • The cytokines function in several ways, primarily to:

activate macrophages

stimulate CD8 lymphocytes to release IL-2 that drives proliferation and the subsequent maturation of the clone into Cytotoxic T-cells

inhibit Th2 cells functions (by IFN-γ)

 

2.  Th2 Cells

  • Produce cytokines (IL-4, TGF-β, IL-10)
  • The cytokines function in several ways, primarily to:

-stimulate B cells

-stimulate differentiation and activation of eosinophils

-inhibit Th1 functions

B cells are divided into two types:

1.  Plasma B Cells

  • Activated B cell that synthesizes immunoglobulins

2.  Memory B Cells

  • Formed from activated B cells that are specific to the antigen encountered during the primary immune response
  • Has a long life spaon — responds quickly following a second exposure to the same antigen

Process of B-Cell Maturation

  • B-cell engulfs antigen and digests it
  • It then displays antigen fragments bound to its unique MHC molecules
  • The combination of MHC and antigen attracts the help of a mature, matching T-cell
  • Cytokines secreted by the T-cell help the B-cell multiply and mature into antibody producing plasma cells
  • Immunoglobulins are released into the blood and they lock onto matching antigens
  • The antigen-antibody complexes are then cleared by the complement cascade or by the liver or spleen

Fab region of Immunoglobulins

  • The hypervariable region
  • Part of the immunoglobulin that binds to antigens
  • Each of the variants bind to different antigens

Fc region of Immunoglobulins

  • The membrane-bound region of immunoglobulins

Epitope

  • The unique part of the antigen recognized by the immunoglobulin
  • These epitopes bind with their immunoglobulin in a highly specifc interaction, called induced fit

IgA

  • Dimer
  • Found in mucosal areas (gut, respiratory and urogenital tract)
  • Prevents colonization of pathogens
  • Found in saliva, tears, breast milk

IgD

  • Monomer
  • Functions mainly as an antigen receptor on B-cells
  • Function is less defined than other isotypes

IgE

  • Monomer
  • Binds to allergens and triggers histamine release from mast cells
  • Involved in allergic response
  • Protects against parasitic worms

IgG

  • Monomer
  • In its four forms, provides the majority of Ig-based immunity against invading pathogens
  • Most common type of Ig

IgM

  • Pentamer
  • Expressed on the surface of B-cells and eliminates pathogens in the early stages of B-cell mediated immunity before there is sufficient IgG

Process of Immunologic Initial Acute-Asthma Inflammation

  • B lymphocytes synthesize IgE after exposure to antigen
  • IgE attaches to mast cells and with re-exposure to antigen, they form antigen-Ig complexes
  • These complexes trigger synthesis and release of mediators (histamine, leukotrienes, prostaglandins) from mast cells
  • Results in mucus secretion (and potentially mucus plugs) and bronchoconstriction

Type I Immune/Inflammatory Response

  • Anaphylaxis
  • Asthma, hey fever, hives, etc.
  • Severe reaction to “innocuous” substances (grass, food, etc.)
  • Th2 antigen response, provoking IgE activity
  • Can result in anaphylactic shock

Type II Immune/Inflammatory Response

  • Cytotoxic Reaction
  • Host cells are recognized as “foreign”
  • Ex: host cells altered by drugs are sometimes mistaken by the immune system as foreign proteins and provoke Ig formation –> antigen-Ig reaction triggers complement activation (and its sequelae) and may provoke attack by NK cells
  • Neutrophils and platelets can be altered by drugs, leading to agranulocytosis and thrombocytopenic purpura, respectively
  • Acute Transplantation Rejections

Type III Immune/Inflammatory Response

  • Immune-Complex Reaction
  • Antigen-Ig complexes can activate complement or attach to mast cells and stimulate release of mediators
  • Large antigen-Ig complexes that cannot be cleared are deposited into vessel walls and induce an inflammatory response
  • This is NOT cell mediated
  • Rheumatoid arthritis

Type IV Immune/Inflammatory Response

  • Cell-Mediated Reaction, AKA Delayed Hypersensitivity

Histamine secretion is initiated by:

  • Rise in [Ca2+]i
  • Stimuli include C3a and C5a that interact with specific surface receptors, and the combination of antigen with cell-fixed IgE
  • Also, drugs can cause exocytosis of histamine (morphine, tubocurarine)

Histamine secretion is inhibited by:

  • Rise in [cAMP]i
  • i.e. Epinephrine binding to Gs-PCR on Mast cells

Histamine Functions in the body

Involved in:

  1. Allergic rxns
  2. Inflammation
  3. Local immune responses
  4. Gastric acid secretions (H2-receptors)

Histamine locations in the body

Found in high concentrations in:

  1. Lungs
  2. Skin
  3. GI tract

H1 Receptors

  • Gq-PCR
  • Dilation of blood vessels
  • Bronchoconstriction
  • Type-1 Hypersensitivity
  • Increased vascular permeability
  • Itching

H2 Receptors

  • Gs-PCR
  • Gastric acid secretion

Eicosanoid biosynthesis begins when:

the cell is activated by:

  1. mechanical trauma
  2. cytokines
  3. growth factors
  4. other stimuli

Eicosanoids are divided into two groups:

  • Prostanoids
  1. Prostaglandins
  2. Thromboxanes
  3. Prostacyclins
  • Leukotrienes

COX-1

Arachidonate —> Cyclic Endoperoxides

  • Housekeeping
  • Constitutive

 

COX-2

Arachidonate —> Cyclic Endoperoxides

  • Pathological
  • Inducible
  • Associated with inflammation

Biochemical Pathway of Prostanoids

Phosholipids

Phospholipase A2

Arachidonate

COX-1,2

Cyclic Endoperoxides

Isomerase/Synthase

Prostacyclins, Prostaglandins, Thromboxanes

PGI2

Prostacyclin

  • Acts chiefly to prevent platelet formation and clumping involved in blood clotting
  • Effective vasodilator
  • Actions are opposite of thromboxane

TXA2

Thromboxane

  • Thrombotic
  • Effective vasoconstrictor
  • Actions are opposite of prostacyclin

LTB4

Leukotriene

  • Powerful chemotactic agent for both neutrophils and macrophages
  • Increases production of reactive oxygen species (increased damage)
  • Stimulates proliferation and cytokine release

 

Leukotrienes

  • Responsible for a number of the effects of asthma and allergies
  • Use both paracrine and autocrine
  • Synthesized from arachidonate by lipoxygenase-catalyzed pathways
  • The lipoxygenase pathway is active in leukocytes, including mast cells, eosinophils, neutrophils, monocytes, and basophils

LTC4

Leukotriene

  • Increases mucus production
  • Reduces airway conduction and expiration (bronchoconstriction)
  • Increases vascular permeability

LTD4

Leukotriene

  • Increases mucus production
  • Reduces airway conduction and expiration (bronchoconstriction)
  • Increases vascular permeability

LTE4

Leukotriene

  • Increases mucus production
  • Reduces airway conduction and expiration (bronchoconstriction) — less potent than LTD4 and LTC4, but effects of LTE4 are longer lasting
  • Increases vascular permeability

Lipoxins

  • Anti-inflammatory mediators
  • High affinity antagonists at CysLT1 receptors, to which leukotrienes bind and mediate their smooth muscle contraction and eosinophil chemotactic effects

Platelet Activating Factor

  • Produced by neutrophils, basophils, platelets, and endothelial cells
  • Causes vasodilation and permeability
  • Bronchoconstriction (late phase of asthma)
  • Activation of leukocytes and chemotaxis
  • Aggregation of platelets and release of their granules

IL-1

  • Produced by macrophages and monocytes causing T and B cell activation
  • Pyrogen activation on hypothalamus

IL-2

  • Secreted by T-Helper cells to stimulate the production of T-Helper cells, Cytotoxic T cells, and B cells
  • Activate NK cells (proleukin)

IL-10

  • Secreted by monocytes, Th2 cells, mast cells, and inhibits Th1 cytokine production

IFNα and IFNβ

  • Produced by virus-infected macrophages to stop viral replication in uninfected cells
  • Stimulate T cell growth and activate NK cells
  • Suppress some tumor cells

TNF

  • Stimulate macrophage and neutrophil migration to inflammation and killing of microbes
  • Induces apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesis, and viral replication
  • Induces fever
  • Stimulates macrophages to produce IL-1

Chemokines

  • Associated with recruitment of WBCs to enter tissue
  • Chemotactic cytokines

Complement C3a
Involved in the release of histamine from mast cells and basophils
Complement C5a
An important chemotactic protein, helping recruit inflammatory cells

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