Lesson 61: Chronic inflammatory response and initiation of adaptive immunity

Types of chronic exudates

Granulomatous

lymphoplasmacytic

Acute inflammation

Minutes to days

Granulocyte

Vasodilation, vascular permeability

Fever, leukocytosis

Fibrin

Chronic inflammation

Days to months

neovascularization

low grade fever, weight loss, anemia

Fibrosis

Roles of macrophage in inflammation

1. Phagocytosis

2. Antigen presenting cells '

   1. Cytokine production

Granulomatous exudate

Predominantly macrophage with few lymphocyte and plasma cells

Bodys response when inciting cause is difficult to eliminate

• Fungi

• Parasite

• Mycobacteria

• Foreign body

Gross appearance of granulomatous exudate

Not much of fluid component because little vascular response

Cause tissue to be enlarged or raised, firm, pale

Granuloma

Type of granulomatous inflammation

Distinct aggregate of macrophage that surround and wall off an inciting cause

Over time, become encapsulated with fibrous connective tissue and often has a necrotic center

Clinical significance of granulomatous inflammation

1. Benefit:

Robust mechanism to eliminate or sequester an inciting cause.

Initiation of antigen presentation to include adaptive immunity.

2. Cost:

Infiltration of immune cells impedes organ function. It’s not a good sign; the body’s beginning to concede that containment may be the best option (granulomas)

3. Resolution:

Inciting cause may be eliminated or if containment unsuccessful, the inflammatory process starts again

T-lymphocyte

Host cell killing

Make contact with infected cells or tumor cells and release cytotoxins that result in a protease cascade within the cell

Apoptosis

B-lymphocyte

Antibody production

Produce antibodies specific to cell surface of antigens that are recognized by T-cells, phagocytic cells and other immune processes

Lymphoplasmacytic Exudate

Infiltration of both lymphocytes and plasma cells as they respond to the same type of stimulus

Often associated with viruses, hypersensitivities/immune mediated conditions, toxins, and other intracellular processes

Tissue appears pale and flat with no fluid component

Hard to grossly differentiate from coagulative necrosis and other cellular changes so need microscopy

Clinical significance of granulomatous inflammation

1. Benefit:

Inclusion of host-cell killing and antibody-mediated immunity in the

inflammatory response

2. Cost:

Inflammatory infiltrates often contribute to organ dysfunction (e.g.

inflammatory bowel disease)

3. Resolution:

Will resolve if inciting cause eliminated

Antigen

Definition:

• foreign molecular structure that can initiate an adaptive immune response

• A molecule capable, under appropriate conditions, of inducing an adaptive immune response (Humoral and CMI)

• Can interact with the products of the response

Function

• Initiate adaptive immune response

Examples

• Microbial molecules

• toxins

• abnormal molecules expressed on surface of tumor cells

Antigen presenting cells

Definition

• Cells that present antigens to t lymphocytes

Function

• Present antigen peptide fragments to T-Lymphocyte

• This initiates activation of the T cell

Example

• Dendritic cells

• Macrophage

• B cells

• any nucleated host cell that is infected or a tumor cell

MHC molecule

Definition

• Molecules expressed by APC that can hold antigenic peptide fragments in their grooves

Function

• Enable presenting cells to present antigenic peptife fragments to T-lymphocyte

Example

• Macrophage engulfs microbe and breaks up the microbial proteins into peptides and then puts peptides into these molecules for presenting to T cells

B-Lymphocyte

Definition

• Cells of the adaptive immune system that can respond to antigen and provide a humoral immune response

Function

• Make antibody when become plasma cell

• Pro/semi APC

Example

• Become activated by antigen and then make antibody specific to that antigen

T-Lymphocyte

Definition

• Cells of adaptive immune system that can respond to antigen and provide a cell mediated immune response

Function

• Make cytokines that help other cell

• Kill host infected or tumor cell

Example

• T helper

• Cytotoxic T Lymphocyte

Antigen priming of adaptive immune system

• B cells recognize antigen free in solution

• T cell must have their unique antigen presented to them by another cell

Antigen interaction

Antigen that induced response will be recognized by specific antibody generated by the response

Antigen can be recognized by:

• specific T-lymphocyte via the T cell receptor

• specific B lymphocyte via B cell receptor

• MHC molecule

Properties of good immunogen

• Molecular size: needs to be >1000 daltons to be immunogenic

• Complexity/chemical composition:

  • Simple repeating units are poor immunogen: polymers, carbohydrates, plastics

  • Proteins and glycoproteins are complex molecules and usually good immunogens

  • Lipids and nucleic acid are poor immunogen

• Stability: If the molecule is easily degraded, it wont exits long enough for to be immunogenic

• Foreignness to host: Foreign proteins make the best antigens

Epitopes

AKA Antigenic determinant sites

• portion of a larger immunogenic molecule that actually binds with antibody, the BCR or TCR

• single antigen may have several different epitope.

• each epitope will be recognized by different antibody or BCR/TCR

Protein epitopes

• Can involve primary or secondary elements

• conformational in that the immune responses are dependent on recognizing the proteins in their native or conformation state

  • Once denatured, immunogenicity may be lost

Haptens

Small molecules that by themselves are not immunogenic(cannot elicit immune response)

Has to bind to a larger molecule so that adaptive immune system can recognize it as foreign and respond

HUMORAL immune response

Once antibody is generated, hapten alone can be bound by antibody

Example of haptens

Examples: drugs, hormones, toxins

Penicillin: Might bind albumin (carrier protein) or bind RBCs, for example. Then, can elicit an immune response. If penicillin bound to RBCs, antibodies against the penicillin would result in the destruction of the RBCs. Penicillin acting as a hapten can also result in a Type-I hypersensitivity to penicillin (allergy)

Cross reading antibodies

• Identical or similar epitopes are sometimes found on apparently unrelated molecules

• Antibody generated against on antigen may react with an unrelated antigen(has similar epitope)

Examples of cross reacting antibodies

1. Brucella abortus and Yersinia enterocolitica

2. Some microbial epitopes can be similar to animals own tissue epitope

3. RBC blood type

Natural antibody

• Antibodies against foreign antigens without any known previous infection, vaccination, transfusion exposure to account for it.

• Probably arise due to exposure to antigens (particular epitopes) on harmless bacterial or food that are identical or similar to other epitopes….

• Many bacteria possess cell-wall glycoproteins (gp) with carbohydrate side-chains that are identical to mammalian Red Blood Cell antigens

Microbial antigens

Most important microbial antigen are PROTEIN molecules

Some carbohydrates and lipods from microbes can also be immunogenic

Adaptive immune response can also be generated against helminths and other larger pathogens

Non microbial antigens

Allergens

Molecules expressed on surface of normal cells that could stimulate immune response in another animal

• Ex. RBC glycoprotein antigen, MHC molecules, CD molecules

Major histocompatibility complex molecule

MHC

MHC molecule required for antigen presentation to T-lymphocyte by other cell

Recipient generates an adaptive immune response to foreign MHC molecules expressed by the donor organ/tissue.

• Thus, in the recipient, the MHC molecules are antigenic (seen as foreign)

Cluster of Differentiation molecules

Naming system for Surface molecules on normal immune cell

Each CD denotes a protein with a specific function

Expression of CD on lymphocyte is used to define subset of lymphocyte

ex.

• All mature T lymphocyte express CD3

• All mature T helper cells express CD4

• All mature CTL express CD8