Final Exam - Autoimmunity

Autoimmunity

an inappropriate adaptive immune response, or a loss of self-tolerance, mediated by a large production of autoantibodies and autoreactive T cells. Will usually persist upon activation, and will not be inactivated unless there is complete destruction of the target tissue or organ

autoantibodies, autoreactive T cells

two important components of autoimmunity

Immune thrombocytopenia, Hemolytic anemia, Myasthenia gravis

three Non-inflammatory Autoimmune Diseases

metabolic control

Treatment of organ specific autoimmunity usually involves...

Hashimoto's thyroiditis

an organ specific autoimmune disease which leads to the formation of goiter or hypothyroidism due to an infiltration of the thyroid gland with inflammatory lymphoid cells such as mononuclear phagocytes, lymphocytes, and plasma cells.

mononuclear phagocytes, lymphocytes, plasma cells

three cells that infiltration the thyroid gland in the development of Hashimoto's

Thyroid peroxidase

enzyme found in the thyroid gland that is targeted by antibodies in Hashimoto's thyroiditis. Antibodies also target thyroid cell cytoplasm

Exophthalmos

ocular sign of Hashimoto's disease

Grave's disease

condition where there is an overproduction of thyroid hormone. This causes an enlargement of the thyroid and other symptoms such as exophthalmos, heat tolerance, and anxiety. A common cause of hyperthyroidism.

destruction, stimulation

Hashimoto's and Grave's are different in that Hashimoto's involves thyroid ______, whereas Grave's involves thyroid _____

Anti-inflammatory/immunosuppressive drugs, biological therapy, B cell directed therapies

three approaches to systemic autoimmunity

Systemic lupus erythematosus (SLE)

systemic autoimmune disease where the blood serum reacts with many tissues in the body. One of the dominant antibodies is against cell nuclei.

Chalazion, blepharitis, keratoconjunctivitis sicca, retinal vasculitis

four ocular signs of systemic lupus

Bronchial asthma

autoimmune disease where there is a production of autoantibodies against alpha adrenergic receptors

Guillain Barre syndromea

utoimmune disease where there is a production of autoantibodies against sodium channels.

spermatozoa

Male infertility can occur when autoantibodies are produced against...

Ptosis, diplopia

two ocular signs of myasthenia gravis

dry eye, scleritis, uveitis

three ocular signs of rheumatoid arthritis

15, 30

The chance of developing multiple autoimmune disease is high. For example, ___% of patients having Sjogren's syndrome also have autoimmune hypothyroidism and _____% also have lupus.

Inflammation, decreased tear production, increased tear drainage

three causes of dry eye which can lead to inflammatory cell infiltration and the activation of the ocular surface epithelium

CD4, II

Ocular surface inflammation in dry eye is associated with _____ T cell activation which are activated by MHC class ____ molecules bound to antigen presenting cells. This occurs towards the end of the acute response.

T helper 1 cells

the most abundant subset of T cells seen in dry eye responsible for producing INF gamma and TNF alpha

T helper 2 cells

subset of T cells seen in dry eye responsible for producing IL4, 5, and 13

IL 1, 6, 8

three proinflammatory interleukins detected in the tear film of dry eye patients

Type I hypersensitivity reaction

hypersensitivity reaction where an antigen binds to IgE found on mast cells. This causes the release of proinflammatory granules as well as the activation of phospholipase A2. Phospholipase goes on to produce prostaglandins and leukotrienes.

Histamine, cytokines, heparin

three chemical mediators, upon others, released by mast cells during type I hypersensitivity reaction

Cyclo-oxygenase pathway

pathway that produces prostaglandins in response to phospholipase A2 activation during type I hypersensitivity reactions

Lipoxygenase pathway

pathway that produces leukotrienes in response to phospholipase A2 activation during type I hypersensitivity reactions

IL4 and TH2

two cytokines expressed in patients with allergic conjunctivitis

Sensitization phase

phase of type I hypersensitivity reactions where there is exposure to an allergen and mast cells begin to express IgE in response to the presence of the antigen

Activation phase

phase of type I hypersensitivity reactions where there is subsequent exposure to the antigen and mast cells are activated to release their proinflammatory granules.

Type II hypersensitivity reaction

hypersensitivity reaction that is triggered when an antigen is localized in a particular organ. Results in either the activation of classical complement or antibody dependent cell cytotoxicity. Ie) autoimmune hemolytic anemia

when the autoimmunity is localized in an organ.

Type III hypersensitivity reaction

hypersensitivity reaction occurring when autoimmunity is systemic leading to inflammation mediated by complement activation and phagocyte recruitment in response to the formation of immune complexes. Ie) lupus, RA

TNF alpha

Immune complexes formed in rheumatoid arthritis stimulate the production of...

Type IV hypersensitivity reaction

hypersensitivity reaction which is a cell mediated reaction localized in a particular organ mediated by activation of T cells. Ie) type 1 DM destruction of beta cells

Chromosome 6

chromosome containing an MHC region which is commonly involved in the formation of autoimmune diseases.

HLADR3

HLA gene expressed in Addison's disease

DR3/4

HLA gene associated with type 1 DM

DR4

HLA gene expressed in rheumatoid arthritis

HLA A1, B8, DR3

three HLA genes expressed in SLE (lupus)

HLA B27

GLA gene expressed in ankylosing spondylitis

PTPN22

non-HLA gene contributing to type 1 DM and rheumatoid arthritis

predisposition, environmental trigger, tissue damage

the three stages in the Progression of Autoimmune Disease

T cells and autoantigen

these two components are required for the production of autoantibodies

Cryptic epitopes

epitopes expressed on the surface of APCs which lead to autoimmunity

Primed T cells

T cells who have been expressing accessory molecules such as LFA1 and CD2 in response to an interaction with a microbial antigen. These molecules allow for high affinity binding to autoantigens without a co-stimulatory signal.

Cross reactive antigens

bind to "helpless" B cell's epitopes that are also bound by non-autoreactive T helper cells. This can result in the further proliferation, differentiation, and autoantibody production by autoreactive T cells

Epstein Barr virus

virus that shows direct B cell stimulation causing the production of antibodies and their presentation to naïve autoreactive T cells.

S aureus

frequent infection by this bacteria can cause relapses in autoimmune disease of the upper respiratory tract.

IL2RA

gene that affects the production rate of cytokines which can trigger autoimmune disease

Inf gamma

cytokine that can be taken up into beta cells of the pancreas and destroy them. This can lead to type I DM.

Graves' disease

Overexpression of MHC class II is commonly seen in this autoimmune condition. This results in an overproduction of cytokines that target the thyroid gland.

TNF

cytokine whose blockade will reduce clinical features of SLE (lupus). Suggests its involvement in the development of the autoimmune disease

Myasthenia gravis

autoimmune conditions where acetyl choline receptors on the post synaptic membrane of the neuromuscular junction are blocked. This results in muscle weakness and fatigability. Autoantibodies are also capable of crossing the placenta.

Alpha adrenergic

autoantibodies against these receptors produce bronchial asthma

Sodium channels

autoantibodies against these channels produce Guillain-Barre syndrome

Spermatozoa

autoantibodies against these cells can cause infertility in men

Pernicious anemia

condition where patients are unable to absorb vitamin B12, a vitamin required for hemostasis. This is mediated by an autoantibody which blocks the interaction between intrinsic factor and B12.

Rheumatoid arthritis

condition where autoantibodies stimulate cytokine production within joints. This causes inflammation and erosion of bone and cartilage at the joint mediated by macrophages and fibroblasts.

Terminal galactosec

omponent missing on autoantibody Fc regions allowing for high binding affinity to IgG autoantigens in rheumatoid arthritis

Tnf alpha

cytokine which is produced in rheumatoid arthritisl

Thyroxin

used in the treatment of hypothyroidism

Insulin

used in the treatment of type I DM

Vitamin B12

used in the treatment of pernicious anemia

Cholinesterase inhibitors

used in the treatment of myasthenia gravis

FasL

binds to death receptors found on inflammatory cells to cause apoptosis. Reduces inflammation in autoimmune disease

TGF beta

immunoregulatory cytokine that can be transfected into patients having autoimmune disease.

Infliximaba

murine-human chimeric antibody against TNF alpha in the treatment of RA

Adalimumaba

fully humanized monoclonal antibody against TNF alpha in the treatment of RA

Etanercept

a soluble TNF receptor in the treatment of RA

Certolizumab

a pegylated TNF alpha antibody in the treatment of RA

Methotrexate

an anti-neoplastic that can be combined with TNF alpha antibodies to improve the treatment of RA

Rituximab

B cell depleting drug that is an anti-CD20 monoclonal antibody used in the treatment of RA and MS

Tocilizumab

B cell depleting drug that is a monoclonal antibody against IL-6 receptor used in the treatment of RA

Abatacept

B cell depleting drug that inhibits the costimulatory interaction between T cells and APCs in the treatment of RA

Anakinra

B cell depleting drug that is an IL-1 receptor blocker used in the treatment of RA