Pathophysiology (Ch. 6-9)

Nonspecific barriers

1st: external barriers

2nd: nonspecific barriers, protective proteins, cells, and mechanisms

1st Barrier: Non-specific external defense

• barrier (skin), traps (mucous membranes, cilia, earwax), elimination (coughing, sneezing, urination, diarrhea), unfavorable pH (stomach acid, sweat, saliva, urine), lysozyme enzyme (digests bacterial cell walls, sweat, tears)

2nd Barrier: Innate Immune

Phagocytes and granulocytes

Adaptive barriers

3rd: specialized immune cells

Innate Immune System Cell Types

• phagocytes: engulf pathogens, clean up crew and present antigens to adaptive immune cells.

• granulocytes: Release granules, different cells have different components in granules

Adaptive Immune System Cell Types

humoral response: “in the blood” production of antibodies by B-cells

cellular response: production of cytokines (signals) by CD4+ Helper T cells. CD8+ cytotoxic T-cells (targeted cell killers).

Granulocytes

Release granules of immune cell components

• Neutrophil: most abundant, attack pathogens

• Basophil: accumulate in damaged tissue, release histamine and heparin, recruit other cells to the site

• Eosinophil: mucus membranes, kill parasites

• Mast cells: release histamine, allergy and inflammation

• NK cells: cytotoxic recognize cells lacking cell identifiers (identifiers often lost during viral infections and cancer)

Phagocytic cells

• Monocyte: turn into macrophages, are phagocytic cells

• Macrophages: phagocytic cells ready to be activated

• Dendritic: “resident” phagocytes

Pattern recognition receptors (PRRs)

found on the surfaces of innate immune cells

• Monitor for cellular damage and microorganisms, recognize common molecules

• Pathogen-associated molecular patterns (PAMPs)

• Damage-associated molecular patterns (DAMPs)

Inflammation

Triggered by cellular damage and the release of cytokines from immune cells

Components of inflammation: Vasodilation, increased vascular permeability

and leakage, White blood cell adherence to the inner walls of the vessels, and

migration through the blood vessels

Hallmarks: Redness, heat, swelling, pain, loss of function

Wound Repair

hemostasis (vascular spasm (constriction), platelet plug formation (primary), and the coagulation cascade (secondary)), clot (containment of damaged tissue/infection), pus (accumulation of dead neutrophils, bacteria, cellular debris, and tissue fluid), pain limits use of body part so it can heal

Antimicrobial peptides

inhibit microbial reproduction and provide short-term, nonspecific resistance to pathogenic bacteria and viruses

Complement System

Plasma proteins made by the liver that act in a cascade of reactions to attack

extracellular forms of pathogens in extracellular spaces/blood.

Three pathways for activation (of Complement System)

Classical pathway, lectin pathway, alternative pathway

Functions of Complement System

• Recruitment of inflammatory cells

• Opsonization and facilitating phagocytosis

• Lysis of pathogen cells

Opsonins

Coat the surface of bacteria and increase their susceptibility to being phagocytized and killed by inflammatory cells

• C3b (opsonin)

Chemotactic factors

Diffuse from a site of inflammation and attract phagocytic cells to that site

• C3a (anaphylatoxin)

Anaphylatoxin

Induce rapid degranulation of mast cells, a major cellular component of inflammation

• C5a (anaphylatoxin and chemotactic factors)

Fever

an abnormal elevation of body temperature

• Promotes interferon activity

• Elevates metabolic rate and accelerates tissue repair

• Inhibits reproduction of bacteria and viruses

Fever is usually triggered by exogenous pyrogens—fever-producing agents

• Glycolipids on bacterial and viral surfaces

Endogenous pyrogens

• These raise the hypothalamic set point for body temperature

NK cells

attack and destroy bacteria, transplanted tissue, host cells infected with viruses or cancer cells

T Cells

mature in thymus

CD4+ T cells (T-helper cells, Th Cells)

Helper cells, can help with a variety of adaptive immune responses by activating other cell types

Cytotoxic T cells ( CD8+ T Cells)

Kills infected host cells

B Cells

differentiate into plasma cells, make antibodies

MHC Class I

Presents endogenous (intracellular) antigens

• On all cells, presents inside contents to monitor for virus/intracellular pathogen

• Important for organ donor matches

MHC Class II

Present exogenous antigens

• Only on antigen presenting cells

• Shows bits of antigen to cells in the adaptive immune system

How Major Histocompatibility (MHC)

If no MHC and stressed out-signals - Virus infected so NK cells kill it

Types of antibodies

IgA, IgD, IgE, IgG, IgM

Acquisition of Immunity

Natural passive (breastfeeding), natural active (immunity gained through illness and recovery), artificial passive (immunity gained through antibodies harvested from another person or animal), artificial active (immunity acquired through vaccine)

Cytokines

• Responsible for activating other cells and regulating the inflammatory response

• Chemokines: chemotaxis; attract leukocytes to sites of inflammation

• Interleukins (ILs)- Alter behavior of cells

Toll-like receptor 4 (TLR-4)

recognizes LPS

• Also binds S100 proteins and histones

• DAMPs associated with cell damage/injury and (S100) certain cancers.

activation of TLRs initiates a cascade of intracellular signaling pathways (activation of NF-κB (nuclear factor kappa-light-chain-enhancer)

NF-κB activation

releases inflammatory cytokines including: TNF-α (tumor necrosis factor alpha), Interleukins (ILs), and interferons (IFNs).

Complement System components

opsonin (C3b): coat the surface of bacteria and increase their susceptibility to being phagocytized and killed by inflammatory cells

chemotactic factors (C3a anaphylatoxin): diffuse from a site of inflammation and attract phagocytic cells to that site

Anaphylatoxins (C5a anaphylatoxin & chemotactic factor) induce rapid degranulation of mast cells, a major cellular component of inflammation.

Antibodies

glycoproteins made by activated B cells (plasma cells)

• Referred to as Immunoglobulin or Ig (There are 5 types: IgA, IgD, IgE, IgG, IgM)

• They are secreted by plasma cells and recognise and bind the antigen that triggered their activation

• Comprised of 2 pairs of peptides (two light chains and two heavy chains, which are linked by Cys-Cys disulphide bridges)

Antigen

any substance that produces an immune response in the body

Epitope

part of an antigen to which an antibody can bind.

• also called antigenic determinant sites

• One antigen can have multiple epitopes

Immunogens

antigens that can initiate the adaptive immune response

Haptens

are small-molecular-weight antigens that are not immunogenic and will not initiate the

adaptive immune response alone

• When bound to proteins they can illicit a response

B Cell Biology

activated when antigen binds to antibodies presented on their cell membranes

undergo rounds of cell division to generate clonal populations of plasma cells and memory cells

• plasma cells secrete antibodies directly

• memory cells are activated upon a second exposure to the same activating antigen

Allergy

Deleterious effects of hypersensitivity to environmental (exogenous) antigens

Autoimmunity

Disturbance in the immunologic tolerance of self-antigens

Immune Deficiency

Reaction insufficient to protect the host

Alloimmunity

Reaction against another individual’s tissues

• Causes- Transfusion reactions, transplant rejection, Fetus issues during pregnancy

• alloantigens: Nonself antigens from members of the same species, Blood group antigens, Histocompatibility antigens

MHC I mismatch

alloimmunity

cause recipient CD8+ T-cells to attack donor tissue

MHC II mismatch

alloimmunity

• Direct - donor APC’s can cause T-cell activation of donor tissue

• Indirect - resident APC’s can present donor alloantigen causing T-cell activation

Hypersensitivity

altered immunologic response to an antigen that results in disease or damage to the host

• duration varies

• can be characterized by the immune mechanism

  • Type 1: IgE mediated, Type 2: tissue-specific reactions, Type 3: Immune complex mediated, Type 4: cell-mediated

Type I Hypersensitivity

IgE mediated

manifestations: GI allergy, skin manifestations, mucosal allergies, lung allergens

Type II Hypersensitivity

Tissue-specific damage caused by antibodies binding to antigens on the surface

of cells

• Symptoms depend on cell type and the effect of antibody binding

Type III Hypersensitivity

Immune complex-mediated

• Antigen-antibody complexes are formed in the circulation and are later deposited in vessel walls or extravascular tissues

• In response to Type II- antibodies, and the damage they cause, Type III antibody complexes activate other inflammatory responses (particularly in blood vessels)

Type IV Hypersensitivity

Cell-mediated hypersensitivity reactions

• Does not involve antibodies

• Cytotoxic T lymphocytes and macrophages

Ex. Graft rejection, Allergic reactions from poison ivy and heavy metals

Immune Deficiencies

Failure of immune mechanisms to function normal

• Increased susceptibility to infections

Primary immune deficiency

congenital, genetic anomaly

Secondary immune deficiency

acquired, caused by another illness or immunosuppressants

Infection

arise when barriers are broken down, or defenses are weakened

factors:

• Communicability, immunogenicity, Infectivity, Pathogenicity, Virulence, Toxigenicity

Bacterial Disease

Bacteremia or the presence of bacteria in the blood can lead to septicemia, where

bacteria are multiplying in the blood, and often triggers sepsis, the body’s response to infection, which can be life-threatening

Viral Disease

viruses are not alive, replication depends on ability to infect host cell, not capable of independent reproduction, virion in protein capsid shell

Fungal Disease

Fungi are large eukaryotic organisms with thick, rigid cell walls, which do not contain peptidoglycan

• mechanisms: tissue damage, mycoses, dermatophytes

The process of infection

1. encounter

2. transmission

3. colonization

4. invasion or penetration

5. dissemination

6. cellular or tissue damage

Stages of Infection

Incubation period: initial exposure to onset of first symptoms

Prodromal stage: occurence of first symptoms

Invasion or acute illness period:

Convalescence:

Pathogenicity

ability to cause disease or illness

Virulence

the degree or intensity of disease producing potential of an organism (the degree of pathogenicity within a group or species)

virulence factor

property of a given microbe that makes the pathogen cause disease, or damage to the host

Exotoxins

Secreted, Soluble, heat-labile, proteins that can be transported to other tissues

• immunogenic

• highly lethal

Endotoxin

largely refers to LPS (Gram-negative cell wall)

Heat-stable, highly toxic, but only weakly immunogenic

• Indirect mechanisms – activate host systems, cells

• Cause general system effects

• not secreted (only released when the organism is lysed)

Antitoxins

antibodies against toxins

Inactivated exotoxins → toxoids (Toxoids still induce an immune response → vaccines)

Mycotoxins

Secondary metabolites of fungi

• common contaminants of food crops

• Aspergillus flavus and A. parasiticus produce carcinogenic aflatoxin

• Stachybotrys produce tissue-damaging satratoxins