Immuno exam 3

Hypersensitivity

Exaggerated reaction of host defense normal immune response that may lead to tissue damage and sometimes death

Type I hypersensitivity

Mediated by the interaction of the allergen, IgE and mast cells as result of allergen exposure.

Sensitization phase

Allergen exposure, IgE synthesis, IgE binding mast cells

Activation phase

Mast cell bound IgE binds to FcE receptor on allergen

Elicitation Phase

Release of mast cell mediators

Mediators

* Preformed = Histamine, Eosinophil chemotactic factor, Heparin \n
* Newly synthesized = Prostaglandins, Leukotrienes

Mediators effects

Vascular system, respiratory system, gut, and skin

Clinical presentations

Allergic Rhinitis, Food allergy, Asthma

Allergic Rhinitis

* most common atopic disorder
* Inhalation of allergens sensitizes IgE mast cells to degranulate mucosa causing vascular permeability and resulting in tissue swelling and nasal blockage
* also sneezing and coughing

Food Allergy

* Ingestion of allergens
* IgE sensitized mast cells degranulate in gut tissue causing muscle contraction and vasodilation causing vomiting and diarrhea

Asthma

* Stimulated by allergens
* chronic obstructive disease of lower respiratory tract

Systemic anaphylaxis

* Re-exposure to allergen via circulation
* Ex. penicillin injection

Radioallergosorbent test (RAST)

* Many test with one blood collection
* Looking for IgE antibody

Skin Prick

* Prick allergen on skin surface
* Positive test = 3mm or greater wheal
* Causes leaky blood vessels
* swelling

Environmental interventions

* Avoid exposure
* wear mask
* move to a less allogeneic area

Pharmacological Agents

Bronchodilators, Antihistamines, Leukotriene modifiers

Bronchodilators

Albuterol Relaxes contraction of smooth muscle

Antihistamines

Block H1 receptors, competitive inhibition

Leukotriene modifiers

Bind to leukotriene receptors

Hyposensitization

* Exposure of allergen via a different route
* Replace IgE with IgG production to have IgG neutralized allergen on rexposure

Acute desinsitization

Injection of a small constant doses to desensitize mast cells

Type ll Hypersensitivity Cytotoxic Reactions

* Initiated by the binding of an Ab directly to an Ag on the surface of cell membrane
* Ab usually involved IgG or IgM
* Formula : (Cell membrane + Ag) + Ab + C’ (complement) (or NK Cell) = cell lysis
* Target cell killed by - Complement mediated cell lysis

Common Examples

* Drug induced hemolytic anemia - Dose of drugs Ab to bind on red blood cell which fix complement and lyse the cell
* Erythroblastosis Fetalis - Rh+ dad and Rh- mother baby is Rh+. First pregnancy body is okay mother makes Ab for Rh+ Second pregnancy mother has Ab will attack Rh+ baby

Type lll Hypersensitivity (Immune complex reactions)

* Immune complex resulting from IgG or IgM to a __**soluble**__ Ag forming an immune complex
* Immune complex associates with a cell membrane
* Activates complement
* Complement inflammation leads to tissue damage
* Formula = (Ab + Ag) + Cell Membrane + complement
* \

Complement mediated inflammation

* Ag + Ab form immune complex
* C3a,C5a
* Chemotaxis occcurs
* Opsonization C3b

Type lll Examples

* Serum Sickness - Results from treatment with immune serum made in horses
* Abs are made from exposure to horse serum Ag

Type lV Hypersensitivity Delayed Type Hypersensitivity

* Mediated by T cells and __**NOT**__ antibody

Sensitization Phase

* First exposure to Ag and sensitization of T cells
* Th1 activate cytotoxic cells, Th17 activate macrophages

Elicitation Phase

Re-exposure to Ag production of cytokines by T cells

Effector Phase

Recruitment and activation of inflammatory cells that cause tissue damage

Type lV Allergens

Metal ions, latex, cosmetics, poison Ivy - act as haptens that bind to skin proteins.

Delayed Hypersensitivity can be Protective

Mycobacterium tuberculosis ,Humoral pathway will not get rid of infection while cytotoxic pathway will eliminate the infection

Autoimmunity general Characteristics

* Failure to maintain self-tolerance
* All pathology explained by Type ll, lll, lV reactions

Tolerance

The state of unresponsiveness to self-antigens

Central Tolerance

Tolerance induced in immature T and B Cells in the primary lymphoid organs (Thymus Bone Marrow) called positive and negative selection

Positive T-cell Selection

* Occurs in cortex
* education of T-cell to self antigen and MHC markers expressed on thymus epithelial cells

Negative T-cell selection

* Occurs in medulla
* Testing T-cell interaction with self- MHC markers and self antigens
* If cell binds to self ag it is neutralized if not it leaves the thymus

If B-cell develops Ab receptor that binds to self Ag one of four things can happen

Negative selection, Receptor editing, Positive selection or anergy (non-responsive cell)

Negative B cell selection

* Occurs in bone marrow
* B-cell deletion or apoptosis

Receptor editing

* V-gene rearrangement

Positive selection

Second chance to make non-self Ab

B-cell anergy

non responsive cell, dies off

AIRE (Autoimmune Regulator gene)

Expressed in thymus epithelial cells and codes for self Ag found outside of thymus, educates T-cells about self

Normal AIRE

Codes for self Ag

Autoimmune

People who lac the AIRE gene cannot Identify T-cells that respond to self-Ag thus cannot leave the thymus and can cause IR

Peripheral Tolerance

Tolerance induced in mature T and B cells that make the peripheral circulation if cells escape the central tolerance mechanisms

Mechanism of Peripheral Tolerance

* APC needed to activate T-cells (dendritic cell)
* Activated by 2 signals

T-cell signal 1

* Recognition by TCR of MHC with Ag peptide

T-cell signal 2

Interaction of the costimulatory molecule B-7 on the APC

B-cells need how many signals?

3

B-cell signal 1

Ag binding to B-cell Ab receptor

B-cell signal 2

Interaction of the CD40L on T-cell with CD40 on B-cell

B-cell signal 3

IL-4

Why do B-cells need T-cells

Need signal from T-cell to bind

Immune Privileged sites

* Sites that do not develop IR to pathogens, tumors or histocompatibility tissue transplants
* Eye,Testes,Ovary,Placenta,Brain

Why do immune privileged sites exists?

* Lack of lymph drainage
* Blood/brain barrier
* Local production of IL-10 immune suppresion molecule

WHy do some people get autoimmune disease

* Genetics
* Diet
* Toxins
* Infections

Genetic susceptibility

* Autoimmunity associated with HLA/MHC complex
* HLA/MHC can trigger autoimmune diseases

Sequestered Ag

* Antigens who stay in place
* Exposed to immune system after serious injury

Molecular mimicry

IR from external Ag, Ab from said response attacks self cells

Polyclonal Activators

Non-specific stimulation of T and B cells from mitogens

Drug induced triggers

Durg bound to cell can cause autoimmune disease

Type l diabetes

* Type ll reaction + Tctl
* caused by insulin

Rheumatoid Arthritits

* Type lll (immune complex) and type lV reaction(macrophage regulation)
* RH+ individual
* Immune system causes damage of synovial capsule

Systemic Lupus Erythematosus

* Type lll reaction
* mediated by Auto-Abs and immune complexes in joints,blood vessels, heart, kidneys, and brain,

Myasthenia Gravis

* Type ll reaction
* Auto-Ab acts as an antagonist that blocks the binding of the acetylcholine to the receptor
* inhibit muscle contractions

Transplant

Organ transfer

Organs come from

Living donors, cadaver, tissue culture, xenotransplantation(organ from other organism ex. pig)

Autograft

Transplant of tissue to the same person (skin, blood,vein, stem cells)

Allograft

Transplant of tissue between two genetically non identical members or the same species

Isograft

Transplant tissue between genetically identical twins

Xenograft

Transplant of tissue from one species to another (pig organs)

Split transplant

* Donor organ divided between two recipients.
* Ex. liver divided between an adult and child

Domino transplant

* Transplantation of a complete set of organs
* lungs and heart donated to cystic fibrosis patient heart from cf patient donated to another.

Rejection Timeline

The same as the timeline observed for a primary and secondary immune response

Tolerance (Rabbit + rat experient)

Rabbit cells were transferred while rat in utero recognizes rat cells as self.

Transfer of Immunity

* Immunity against graft can be transferred by transferring immune cells after a transplant
* Cells commonly transferred include T, B, MØ

MHC/HLA is important to present Ag

By having 6 from mother and 6 from the father 12 total redundancy is pressent.

MHC inheritance

The closer the relationship the more likely a compatible tissue for transplant will be found

Tissue typing

* Use patient serum to look for pre-existing Abs and match MHCs

Why do we check for pre-existing Abs?

If pre-existing Abs are present the transplant will be rejected as the recipient will attack the transplanted cells.

Allogeneic graft survival

Tissue match and immunosuppression therapy

Hyper-acute rejection

* Due to existing Ab, not an IR to the graft
* only occurs due to negligence

Acute Rejection

* Weeks to months long to develop due to recognition of foreign MHC markers and improper immunosuppression.
* Usually Type ll, lll, lV, And cytotoxic reactions

Chronic Rejection

* Months to years directed against major and minor MHC resulting in inflammation
* Kidney/ heart - vascular occlusion(Blockage)
* Lung - Thickening of airways, bronchiole obstruction
* Liver- Fibrosis and bile duct obstruction

Immunosuppression therapy

Lowers immune defenses to avoid rejection

Induction therapy

Strong suppression of IS, especially t-cells prior to transplantation (Knockout)

Maintenance Therapy

Lower doses of immunosuppressive drugs, suboptimal IS function to limit recognition of graft (Balance)

Specific treatments

For acute rejection episodes, resembles induction therapy

Anti-inflammatory drugs

corticosteroids (Induction)

Cytotoxic

DNA/RNA interference (Induction)

Cytokine interfering agents

cyclosporin (maintenance)

Ab therapy

Anti-lymphocyte serum (Induction)

Graves vs Host disease

* Donor cells react to recipient tissue
* Recipient immunosuppressed
* Donor tissue must be immunocompetent to immune cells
* Difference between in MHC

Fetal graft

mom has her own Abs will see baby cells as foreign baby has population of NK cells to protect itself from mothers cells