(13) Autoimmune Diseases

autoimmune disease (type IV hypersensitivity) that is primarily T cell mediated (involving both CD4+ CD8+ T cells) and results in a progressive demyelination of CNS, leading to a loss of neuronal transmission

multiple sclerosis

Is multiple sclerosis systemic or organ specific?

organ specific

(myelin sheath)

What cells/molecules mediate multiple sclerosis?

T cells

(especially CD4+)

What are the main T cells involved in multiple sclerosis?

CD4+ (helper)

What do T cells in multiple sclerosis attack?

myelin sheath

Even though multiple sclerosis is predominantly T cell mediated, the continuous attack of the T cells will result in debris. This debris will now result in antibodies against what protein?

myelin basic protein

What HLA is associated with multiple sclerosis?

HLA-DR2

What type of hypersensitivity reaction is multiple sclerosis?

type IV

form of multiple sclerosis in which myelin is destroyed, action potential is inhibited, and neurological function is decreased

but the immune reaction subsides for a while and neurological function returns slowly as nerves generate more sodium channels to compensate for the loss of action potential

relapsing-remitting form

form of multiple sclerosis in which myelin and axons are destroyed continuously and gradually over time; no periods of remission, no return or restoration of function

chronic progressive form

Pathogenesis of multiple sclerosis is due to both a genetic predisposition and environmental exposure. In addition to being linked to specific HLA-DR2 alleles, multiple sclerosis is also possibly linked to what three viral infections?

EBV, adenovirus-2, hepatitis B

(due to molecular mimicry!)

autoimmune disease (type IV hypersensitivity) that is mostly T cell mediated and involves CD8+ cells destroying beta cells of the pancreatic islets of Langerhans that produce insulin

in the early stages, we see insulitis and lymphocyte infiltrate, and later on, we will see beta cell destruction

type I diabetes mellitus

Is type I diabetes systemic or organ specific?

organ specific

(pancreatic islets, though also has systemic manifestations)

What cells/molecules mediate type I diabetes mellitus?

T cells

What are the main T cells involved in type I diabetes?

CD8+ (cytotoxic)

What do CD8+ T cells attack in type I diabetes?

beta cells in pancreatic islets

Even though multiple sclerosis is predominantly T cell mediated, the continuous attack of the T cells may also result in antibodies being made against what?

insulin

(anti-islet cell antibodies in general)

What HLA is associated with type I diabetes mellitus?

HLA-DR3 and DR4

What type of hypersensitivity reaction is type I diabetes?

type IV

In some cases of type I diabetes, there is a hereditary tendency for beta cell degeneration. It is mostly associated with DR3 and secondarily with DR4, but the relative risk is almost 100 in an individual that 1) is exposed to the right environmental insults (e.g., viral infection resulting in molecular mimicry) and 2) has what two specific alleles?

DR3, DQw8

What is the most common environmental contributing factor to the development of type I diabetes?

viral infection (leading to molecular mimicry)

Why does having type I diabetes mellitus make some patients more likely to have some other autoimmune disorder?

genetic predisposition

systemic autoimmune disease that involves the production of antibodies against dsDNA and other nuclear components like histones

results in antibody-mediated manifestations in the blood vessels, skin, heart, kidneys, joints, and lymph nodes

systemic lupus erythematosis (SLE)

Is systemic lupus erythematosis (SLE) systemic or organ specific?

systemic

What cells/molecules mediate systemic lupus erythematosis (SLE)?

antibodies

What is the main antibody produced in systemic lupus erythematosis (SLE)?

anti-nuclear antibody (ANA)

What do antibodies in systemic lupus erythematosis (SLE) attack?

dsDNA and histones

What HLA is associated with systemic lupus erythematosis (SLE)?

HLA-DR2 and DR3

What type of hypersensitivity reaction is systemic lupus erythematosis (SLE)?

type III

(deals with antibody-antigen complexes)

People with SLE often have deficiencies in what proteins?

complement

(such as C1, C2, C3b, or C4b, resulting in poor removal of immune complexes)

What is an example of an environmental trigger for SLE?

UV radiation

ANAs in SLE form soluble immune complexes with their antigens and get deposited in tissues, resulting in ____. Therefore, complement is activated and leukocytes and other phagocytes are attracted.

inflammation

How does SLE affect the blood vessels?

vasculitis

(since DNA in endothelial cells in vessels are being attacked)

How does SLE affect the skin?

butterfly (malar) rash, photosensitivity

How does SLE affect the heart?

pericarditis

(ANAs trigger inflammation of the pericardium)

How does SLE affect the kidneys?

glomerulonephritis

How does SLE affect the joints?

arthritis

How does SLE affect the lymph nodes?

lymphadenopathy

(swelling of the lymph nodes)

20% of patients with SLE have what two ocular manifestations?

dry eye, retinopathy

Why do patients with SLE often have dry eye? (due to keratoconjunctivitis)

lacrimal gland is damaged

(may also be due to secondary Sjogren's syndrome)

Why do patients with SLE often have retinopathy? (manifesting as cotton wool spots)

due to vasculitis

Which autoimmune disorder is often associated with SLE?

Sjogren's syndrome

systemic autoimmune disease that involves inflammatory destruction of exocrine glands; several secretory glands may be affected, such as the salivary glands and lacrimal gland

Sjogren's syndrome

Is Sjögren's syndrome systemic or organ specific?

systemic

(but mostly exocrine glands)

What cells/molecules mediate Sjögren's syndrome?

antibodies

(anti-Ro, anti-La, rheumatoid factor, ANAs)

What do antibodies in Sjögren's syndrome attack?

SS-A (Ro) and SS-B (La) RNA-protein complexes

What two exocrine glands are most commonly affected in Sjögren's syndrome?

salivary, lacrimal

What are two common symptoms of Sjögren's syndrome?

dry mouth, dry eye

What eye condition commonly results from Sjögren's syndrome?

keratoconjunctivitis (causing dry eye)

What HLA is associated with Sjögren's syndrome?

HLA-B8

What type of hypersensitivity reaction is Sjögren's syndrome?

type II or III hypersensitivity

(he didn't say, just found this on the Internet)

What 3 other systemic autoimmune diseases are commonly associated with Sjögren's syndrome?

SLE, RA, scleroderma

systemic autoimmune disease of the connective tissue leading to fibrosis, arthritis, and arteritis, affecting the skin, vascular system, GI, lungs, and kidney

**also called systemic sclerosis

scleroderma

Is scleroderma systemic or organ specific?

systemic

(connective tissue)

What cells/molecules mediate scleroderma?

antibodies and T cells

What are the main T cells involved in scleroderma?

CD4+

(activate macrophages and mast cells, which release IL-1, TGF-B, PDGF, and FGF)

What is the main antibody produced in scleroderma?

ANA

(anti-nuclear antibody, same as lupus)

What do antibodies in scleroderma attack?

topoisomerase, RNA polymerase, centromeres

With systemic sclerosis, there is some sort of trigger event in an individual with a genetic predisposition that injures blood vessels and activates lymphocytes, especially CD4+ T cells. They go on to activate macrophages and mast cells, which together release which 4 main cytokines?

IL-1, TGF-B, PDGF, FGF

With systemic sclerosis, there is some sort of trigger event in an individual with a genetic predisposition that injures blood vessels activates lymphocytes, especially CD4+ T cells. They go on to activate macrophages and mast cells, which together release IL-1, TGF-B, PDGF, and FGF. These cytokines go on to activate what other cells?

fibroblasts

(causes them to proliferate and secrete of ECM proteins, leading to fibrosis)

What HLA is associated with scleroderma?

HLA-D types

(he didn't say, just found this on the Internet)

What type of hypersensitivity reaction is scleroderma?

type III hypersensitivity

(he didn't say, just found this on the Internet)

systemic autoimmune disease that is both antibody and T cell mediated that could be type III and type IV hypersensitivity; characterized by chronic inflammation of the synovium and other connective tissues, initiated by the deposition of immune complexes and sustained by chronic inflammatory cells

rheumatoid arthritis

Is rheumatoid arthritis systemic or organ specific?

systemic

What cells/molecules mediate rheumatoid arthritis?

antibodies and T cells

(but mostly T cells)

What is the main antibody produced in rheumatoid arthritis?

rheumatoid factor (RF) and IgG

What are the main T cells involved in rheumatoid arthritis?

CD4+ (helper)

What do antibodies in rheumatoid arthritis attack?

synovium and other CT

What HLA is associated with rheumatoid arthritis?

HLA-DR4

What type of hypersensitivity reaction is rheumatoid arthritis?

type III and type IV

What initiates the chronic inflammation in rheumatoid arthritis?

deposition of immune complexes

(and then the resulting inflammatory reaction is sustained by chronic inflammatory cells)

There is very similar systemic and ocular presentation between RA, SLE, and systemic sclerosis due to their association with what other systemic autoimmune disease?

Sjogren's syndrome

What is the underlying environmental contributing factor to the development of rheumatoid arthritis?

viral infection (leading to molecular mimicry)

In the pathogenesis of rheumatoid arthritis, there is some sort of viral infection that leads to molecular mimicry. The body fights that infection off, but CD4+ T cells are still activated and RF and IgG are still present. The T cells start going "rogue" and activating macrophages and B cells (causing Ig class switch). When they activate macrophages, what two cytokines are released to induce endothelial activation and stimulation of fibroblasts, chondrocytes, and synovial cells?

IL-1, TNF

(triggers rolling, firm adhesion, and extravasation to draw in neutrophils)

In the pathogenesis of rheumatoid arthritis, there is some sort of viral infection that leads to molecular mimicry. The body fights that infection off, but CD4+ T cells are still activated and RF and IgG are still present. The T cells start going "rogue" and activating macrophages and B cells (causing Ig class switch). When they activate macrophages, these release IL-1 and TNF to activate endothelial cells and also stimulate what other 3 cells to proliferate and release enzymes?

fibroblasts, chondrocytes, synovial cells

(those enzymes start breaking down proteins and cells in that region)

anti-IgG antibody (typically sIgM) found in rheumatoid arthritis patients that bind to IgG (via the Fc portion) to form immune complexes, which can lodge in tissues and trigger complement activation and other inflammatory responses (in addition to the effects of CD4+ T cells)

rheumatoid factor (RF)

inflamed fibrovascular tissue that results from the conglomeration of all the inflammatory responses in rheumatoid arthritis, including destruction of bone (due to increased osteoclast activity) and cartilage, fibrosis, and ankylosis

pannus

What does a pannus in rheumatoid arthritis consist of? (4)

**has the potential to invade surrounding tissues, including bone, cartilage, and tendon

fibroblasts, macrophages, T cells, plasma cells

Does rheumatoid arthritis involve increased or decreased osteoclast activity?

increased

True or false: Just because you have rheumatoid factor doesn't mean you'll get rheumatoid arthritis.

true

True or false: Just because you have rheumatoid arthritis doesn't mean you'll have rheumatoid factor.

true

True or false: Titers of RF are directly proportional with severity and occurrence of rheumatoid arthritis.

false

(doesn't always correlate)

Which of the following diseases is ONLY antibody mediated?

A. Hashimoto's thyroiditis

B. Graves disease

C. Multiple sclerosis

D. Type I diabetes

E. Rheumatoid arthritis

B

autoimmune treatment that involves the suppression of specific systemic immune responses by oral administration of the antigen to induce Th3 cells or systemic T cell tolerance

oral tolerance

In low dose oral tolerance treatments for autoimmune disorders, oral administration of the antigen activates which specific regulatory T cells?

**generated from naive T cells in the periphery (MALT)

Th3 cells

In low dose oral tolerance treatments for autoimmune disorders, oral administration of the antigen activates Th3 regulatory T cells, which produce what cytokine?

TGF-B

In low dose oral tolerance treatments for autoimmune disorders, oral administration of the antigen activates Th3 regulatory T cells, which produce TGF-B. What are the two effects of TGF-B?

Th1 and Th2 suppression, IgA isotype switch

In high dose oral tolerance treatments for autoimmune disorders, patients are basically given mega doses of the antigen in order to overstimulate T cells, leading to what?

clonal exhaustion or anergy

(results in systemic T cell tolerance, since they've been overstimulated)

Which oral tolerance treatments result in Th3 cell activation: low dose or high dose?

low dose

Which oral tolerance treatments result in systemic T cell tolerance via clonal exhaustion or anergy: low dose or high dose?

high dose