04-26-12 Part B Autoimmune Diseases

04-12-12 Part B Autoimmune DiseasesEffector mechanisms of autoimmune disease

Endocrine glands as special targets for autoimmunityThyroid gland (Grave’s disease, etc)Islets of Langerhans (Diabetes)Adrenal gland (Addison’s disease)

Systemic autoimmune diseases - autoimmunityagainst common autoantigens (SLE)

Rheumatoid diseases (rheumatoid arthritis)

Autoimmune diseases of the nervous system (MS andmyasthenia gravis)

Genetic and environmental factors that predispose toautoimmune disease – breaking T cell tolerance

Autoimmune disease

Negative selection eliminates self reactive lymphocytes

Autoimmune diseases caused by body respondingto self antigens; failure of self-tolerance

Relatively common; 5% of population (7-8 people in class)

Caused by self-reactive Abs or inflammatory T cells

MHC genes involved; genetically based

Common sources for autoimmune Ags:Reaction to bacterial and viral Ags similar to self Ags

immune system can’t discriminateTissue injury (eg heart attack) can release self Ags

creating autoantibodies

The effectormechanisms of autoimmunity

resemble thoseof certain

hypersensitivityreactions

(P13.2)

(Type II)

Figure 11-2RBC destructionin autoimmune

hemolytic anemia(P13.3)

Figure 11-3

Autoantibodies specific for type IV collagenreact with the base membrane of kidney

glomeruli, causing Goodpasture's syndrome(P13.4)

Endocrine glands secrete tissue-specific proteins that makelikely autoimmune targets.

Hormone secretion into the blood makes endocrine cells highly vascularized, facilitating interactions with immunecells and molecules.

Loss of endocrine function has drastic systemic effects, causing disease and death.

Autoimmune diseases target a single type of epithelial cellwithin the endocrine gland, called “organ-specificautoimmune diseases”

Figure 11-4

(P13.5)

Figure 11-5Grave's Disease(P13.6)

Chronic thyroiditis (Hashimoto disease)

Thyroid loses capacity to make thyroid hormones

CD4 TH1 response favors cell-mediated effectors

Lymphocytes infiltrate and destroy thyroid tissues

Patients become hypothyroid, can’t make thyroid hormones

Ectopic lymphoid tissue can form at sites inflamed byautoimmune disease = “tertiary lymphoid” organ

Lymphoid neogenesis resembles formation and function of secondary lymphoid tissue but without lymphatics or capsule

Hashimoto's thyroiditis (P13.7)

Figure 11-8

Pancreas from a patient with Type 1insulin-dependent diabetes mellitus

(destruction of islet cells -cells)(P.13.9)

Note infiltration of the isletby lymphocytes

Figure 11-1 part 2 of 3

The effector mechanisms of autoimmunity resemble thoseof certain hypersensitivity reactions (P13.2)

(Type III)

Glomerulonephritis(22.7)

Immune complex deposition in the basement membrane of kidney glomeruli in systemic lupus erythematosus (P13.10)

neutrophils

Fluorescent anti-Ig

antibodies

Figure 11-10The chacracteristicfacial rash of lupus

erythromatosusis caused by deposition of

immune complexesin the skin

(P13.11)

Rheumatic diseases are autoimmune in nature (P13.12)

Figure 11-1 part 3 of 3

The effector mechanisms of autoimmunity resemble thoseof certain hypersensitivity reactions (P13.2)

(Type IV)

Figure 11-12Rheumatoid arthritis

is caused by inflammation of

the joints exacerbated by rheumatoid factor(anti-immunoglobulin

antibodies)(P13.13)

Figure 11-13

Treatment of rheumatoid arthritis with

anti-TNR-(P13.14)

Killing of B cells by anti-CD20 antibody and NK cells (P13.15)

Figure 11-15

Diseases mediated by antibodies against cell-surface receptors (P13.17)

Figure 11-14

Myasthenia gravis is caused by autoantibodiesagainst the acetylcholine receptor (P13.16)

Genetic and Environmental Factors and Autoimmune Disease

All autoimmune diseases involve breaking T-cell tolerance

Incomplete deletion of self-reactive T cells in the thymuscauses autoimmune disease

Regulatory T cells protect cells/tissues from autoimmunity

HLA is the dominant genetic factor affecting susceptibilityto autoimmune disease

Noninfectious environmental factors (eg smoking)influence the course of autoimmune disease

Loss of oral tolerance leads to inflammation, autoimmunity

Infections can trigger autoimmune disease

Figure 11-16

Arrest and death of autoreactive B cells in secondary lymphoid tissue (P13.19)

Figure 11-21

CTLA-4 is involved in the action of regulatory T cells (P13.22)

Figure 11-28

Celiac disease is caused by inflammation of the smallintestines due to CD4 T cells responding to peptides

derived from wheat gluten(P12.40)

Celiac disease = Gluten-sensitive enteropathyan environmentally induced autoimmune diseasewith genetic predisposition for certain HLA types

GlnGlu

Figure 11-29

Antibodies against streptococcal cell-wall antigenscross-react with antigens on heart tissue (P13.31)

Molecularmimicry

Treatment of autoimmune diseasesImmunosuppressant (eg cyclosporins)

Anti-inflammatory drugs (eg steroids)

Replacement therapy (eg insulin, thyroid hormone)

eg. including transplantation of pancreatic insulin-producing cells for insulin-dependent diabetes

Feeding or oral tolerance (induce tolerance to antigen)

Feed insulin for diabetes

Collagen for rheumatoid arthritis

Cause local intestinal immune response,

down regulation of antigen receptors

deletion of immune cells

Figure 11-37(P11.37)