Immune systems

increased propensity to develop immediate hypersensitivity reactions

-> higer levels of serum IgEmore Il-4 producilng TH2

TH2 cells and IgE

IL-4, IL-5, and IL-13

Local or systemic reaction to predisposed antigen

Mast cells, basophils, eosinophils

Outcome varies from mild to fatal

Vasoactive amines , Lipid mediators, Cytokines

NOTE: 20% to 30% of immediate hypersensitivity reactions are triggered by non-antigenic stimuli such as temperature extremes and exercise, and do not involve TH2 cells or IgE

dendrictic cells, macrophages, B cells

dendritic cells -> initiating t cell response

express high levels of MHC

eraly defense against intracellular microbial infections

innate immunity

recognize self class I MCH

B (bone marrow derived) lymphocytes produce antibodies

Humoral immunity

10-20% of ciculating peripheral lymphocytes

IN ORDER TO RECOGNISE ANTIGEN THEY DON’T NEED MHC and therefor can react to more chemical structures than T cells

T cells have TCR, B cells have antibodies!!!

B cell antigen receptor is composed of membrane IgM and signaling proteins =BCR

On APC, Macrophages, DC, B cells

For the EXTRACELLULAR proteins

Binds to CD4+

on all NUCLEATED cells

For the INTRACELLULAR antigents

Binds to CD8+

Cytotoxic killing

60% to 70% of the lymphocytes in peripheral blood

major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones

T cells only recognize antigens presented ny other cells (APC) with TCR (T cell receptor)

CD4 Helper cells (50-60% of T cells)

CD8 Cytotoxic cell (40% of T cells)

CD4- and CD8- T cells recognize non protein molecules (unknown function)

Lymphocytes and their products including antibodies

Ability to recognise a vast array of foreign substances

Humoral immunity: B lymphocytes and antibodies

Cell-mediated immunity: T lymphocytes

inflammatory response

viral defense

Epithelial barrier that block the entry of microbes

Phagocytic cells

Dendritic cells

Natural Killer cells (NK)

Plasma proteins (complement system)

PAMPs, DAMPS receptors located in all the cellular compartments where pathogens may be present

Other receptors: CLRs important for detection of fungi,...

5-30 minutes

Vasoactive amines (histamine)

Lipid mediators (PGD2, LTC4,LTD4)

Vasodilatation

Smooth muscle constriction

It lasts for an hour

2-8 hours

Neutrophis, eosinophilsand th2 cells, cytokines

Inflammation and tissue destruction

Can last for several days

Hay fever

Asthma

Atopic dermatitis

Anaphylactic shock

Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surface of cells or other tissue components.

The antigens may be normal molecules intrinsic to cell membranes or in the extracellular matrix, or they may be adsorbed exogenous antigens (e.g., a drug metabolite).

Antigen–antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation.

3= antigen + antybody + complement

The antigens that form immune complexes may be exogenous, such as a foreign protein that is injected or produced by an infectious microbe, or endogenous, if the individual produces antibody against self antigens (autoimmunity). Preferentially involve the kidney (glomerulonephritis), joints (arthritis), and small blood vessels (vasculitis)

Systemic Immune Complex Disease: Formation of Immune Complexes, Deposition of Immune Complexes, Inflammation and Tissue Injury

Local immune complex disease: Arthus reaction

Two types of T cell reactions are capable of causing tissue injury and disease:

(1) cytokine-mediated inflammation, in which the cytokines are produced mainly by CD4+ T cells

(2) direct cell cytotoxicity, mediated by CD8+ T cells

4T= T lymphocytes, TBC, Touch, Transplantation rejection

the recipient’s immune system recognizes the graft as foreign and attacks it. The major antigenic differences between a donor and

recipient that result in rejection of transplants are differences in HLA alleles

Note: Before allografting, test for histocompatibility using HLA antigens!

Grafting one part of the body to another location in the same individuals. There is no chance of rejection. It includes skin graft, taking vein from leg to use in a heart surgery.

Grafting between two non-identical member of same species but not same genotypes. It includes the transplantation of heart, kidney, lung etc, from a members who donate their organs. Anti - rejection drugs or immunosuppressant need to be taken to prevent the body from rejecting a transplanted organ.

Grafting between two individuals, are identically twins or genetically same. Since, they have the same genetics, there is no graft rejection.

Grafting between two individuals of different species. Most commonly from animal to man such as pig heart valve used to replace human. There is more chance of graft rejection and to reduce the rejection, person might need immunosuppressant as in allografts.

the graft antigens are presented to the hosts T-lymphocytes by graft APC

graft antigens are picked up by host APCs, processed and presented to host T cells.

Mediated by transplanted T lymphocytes

Most often a complication of bone marrow transplantation

Organs most often affected: ◦ Skin—exfoliative dermatitis ◦ Intestine—malabsorption and diarrhea ◦ Liver—jaundice

related to certain HLA-DR haplotypes

autoantibodies

SLE, rheumatic fever, rheumatoid arthritis, systemic sclerosis, Sjögren syndrome, polyarteritis nodosa

• –  Multiple sclerosis—CNS

• –  Hashimoto’s thyroiditis, Graves’ disease—thyroid

• –  Autoimmune hemolytic anemia—blood

• –  Pemphigus vulgaris—skin

• –  Myasthenia gravis—muscle

mature lymphocytes that recognise self antigens in peripheral tissues become functionally inactive (anergic), or are suppressed by regulatory T lymphocytes, or die by apoptosis.

• Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often progressive.

• The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response.

systemic

caused by ANAs

1. Anti-nuclear antibodies (ANA) to: a) DNA b) histones c) non histone proteins bound to RNA d) nuclear antigenes

2. Other autoantibodies

• Geneticfactors:familialassociation,HLA

association, other genes

• Enviromentalfactors:UVlight,sexhormons,drugs

• Immunologic factors: defective elimination of self- reactive B cells, defects in peripheral tolerance, defects in CD4+ tolerance, large amount of IFN-, other cytokines ...

- the most common cause of death is renal failure -

• Up to 50% of SLE patients have significant renal involvement, mostly in a form of glomerular disease:

1. Minimal mesangial lupus nephritis (class I)

2. Mesangial proliferative lupus nephritis (class II)

3. Focal lupus nephritis (class III)

4. Diffuse lupus nephritis (class IV)

5. Membranous lupus nephritis (class V)

6. Advanced sclerosing lupus nephritis (class VI)

• A, Focal proliferative glomerulonephritis

• B, Diffuse proliferative glomerulonephritis

• C, Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes

• D, Electron micrograph

• E, Deposition of IgG antibody - immunofluorescence.

Sjögren syndrome is a chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary glands

It occurs as an isolated disorder (primary form), also known as the sicca syndrome, or more often in association with another autoimmune disease(secondary form). Among the associated disorders, rheumatoid arthritis is the most common.

antibodies directed against twzo antigens, SS-A (Ro) and SS-B (La)

• About 75% of patients have rheumatoid factor (an antibody reactive with self IgG)

• pathogenesisofSjögrensyndromeremainsobscure

• aberrant T-cell and B-cell activation are both implicated (the initiating trigger may be a viral infection which causes local cell death and release of tissue self antigens)

• Keratoconjunctivitis

• Xerostomia

• Parotid gland enlargement

• Epistaxis, recurrent bronchitis, pneumonitis, atrophy of oral mucosa, difficulty in swallowing food, ...

• these patients are at high risk for development of B-cell lymphomas

• Systemic sclerosis (scleroderma) is an autoimmune disorder characterized by progressive fibrosis involving the skin, gastrointestinal tract, and other tissues.

• Diffuse systemic sclerosis – (ANA Ab against DNA topoisomerase I)

  • Limitedsclerosis– (anticentromere Ab - CREST syndrome)

95%

begins infingers

edema and perivascular infiltrates

capilaries and small a.

fibrosis of dermis

atrhophy of epidermis

• Calcinosis

• Raynaudphenomenon

• Esophagealdysmotility

• Sclerodactyly

• Telangiectasia

90%

• Most severe in esophagus – rubber-like inflexibility

• Gastroesophageal reflux, Barret metaplasia, strictures

• Malabsorption syndrome

• a newly recognized disorder characterized by tissue infiltrates dominated by IgG4 antibody- producing plasma cells and lymphocytes, particularly T cells, storiform fibrosis, obliterative phlebitis, and usually increased serum IgG4.

• pathogenesis of this condition is not understood

congenital; inherited

aquired

-> cancer, diabetes, metabolic diseases, malnutrition, chronic infection, chemotherapy and radiation therapy, immunosuppressive drugs

from HIV

infects CD4+

p24 capsid to diagnose HIV

Loss of CD4+ T cells is mainly because of infection of the cells and the direct cytopathic

effects of the replicating virus (In infected individuals, approximately 100 billion new viral particles are produced every

day, and 1 to 2 billion CD4+ T cells die each day).

As the disease progresses, renewal of CD4+ T cells cannot keep up with their loss.

• -  Acute (early) infection is characterized by infection of memo20ry CD4+ T cells (which express CCR5) in mucosal lymphoid tissues, and death of many infected cells.

• -  Mucosal infection is followed by dissemination of the virus and the development of host immune responses.

• -  Viral replication leads to viremia and widespread seeding of lymphoid tissue. The viremia is controlled by the host immune response, and the patient then enters a phase of clinical latency.

Candidiasis

• Lymphoma of lymph nodes or GI tract, orbit, lungs (B cell lymphoma)

• Lymphoma of the CNS

• Hodgkin lymphoma

• Kaposi’s sarcoma

• Cervical cancer

• Anal cancer

deposits of fibrillar improperly beta folded proteins in ECM

1. AL (amyloid light chain)– primary

   amyloidosis & plasma cell proliferation

2. AA (amyloid associated) protein related to

   chronic inflammation & tumors

3. A beta amyloid protein – Alzheimer’s disease

1. Transthyretin – ATTR protein – inherited mutations & senile amyloidosis

2. beta 2-microglobulin - hemodialysis

1. Systemic (generalised) amyloidosis

2. Hereditary amyloidosis

3. Localised amyloidosis

AL amyloid light chain (multiple myeloma, B lymphoma)

beta 2 microglobulin (hemodialysis- associated) AA protein (chronic inflammatory conditions)

• Abeta -2 amyloid protein Alzheimer disease

• Calcitonin Medullary carcinoma

• Islets amyloid peptide in Langerhans Type 2 diabetes

• Isolated atrial amyloidosis

• Amyloid of aging (senile cardiac amyloidosis)

• The organ is frequently enlarged

• Gray tissue with waxy firm consistency

• Extracellular eosinophilic – pink or red colour, amorphous, hyaline deposits

• Deposits eventually cause pressure atrophy