Overview of Autoimmune Diseases

What is the difference between Grave's disease and Hashimito's Thyroiditis?

*Graves:* Autoantibodies target a receptor and stimulate it before causing its destruction *Hashimotos:* Destruction occurs w/o stimulation

What causes sclerodactyly?

*TGF-β* Causes extensive deposition of dense collagen and subcutaneous fibrosis, which causes immobilized fingers, creating a claw-like flexion deformity

Idiopathic Thrombocytopenic Purpura (ITP)

- *Antibodies to fibrinogen/ vWF receptors on platelets, glycoprotein IIb/IIIa, Ib/IX* - Depletion of platelets resulting in hemorrhage - Type II hypersensitivity

What triggers the immune response in Celiac disease?

Gliadin (wheat proteins)

Grave's Disease

An autoimmune disorder that is caused by *hyperthyroidism* and is characterized by goiter and/or exophthalmos

Describe the pathophysiology of Grave's disease.

- *Auto-antibodies will target thyroid-stimulating hormone receptors (TSHR)*, which *stimulates the thyroid gland* to produce more thyroid hormone - Thyroid hormones accumulate in the blood (overactivity)

Goodpasture's Syndrome

- *Autoantibodies against alveolar and glomerular basement membrane proteins* - Deposits of antibody in kidney, lung - Type II hypersensitivity

Describe type II hypersensitivity reaction in SLE.

- *IgG or IgM antibodies bind to antigens on cell surfaces* (ex. red blood cells) which can trigger inflammation or interfere with normal function - Can cause complement-mediated lysis, opsonization, antibody-dependent cell cytotoxicity, and antibody-mediated cellular dysfunction

Describe type III hypersensitivity reaction in rheumatoid arthritis sclerosis.

- *Immune complexes form w/ citrullinated proteins*, which accumulates in the synovial fluid - Deposits in tissue activate complement system → joint inflammation and injury

Limited Systemic Sclerosis

- *Mild skin involvement*, often confined to fingers & face. - Involvement of viscera occurs late, so the disease generally follows a benign course = *CREST syndrome*

Pannus

- *Thick, swollen synovial membrane w/ granulation tissue* - Consists of fibroblasts, myofibroblasts, and inflammatory cells

Raynaud's Phenomenon

- A peripheral arterial occlusive disease in which intermittent attacks are triggered by cold or stress - Causes the blood vessels to narrow during cold temperatures. When this happens, blood can't get to the surface of the skin and the affected areas turn white and blue

Anti-Nuclear Antibodies (ANA)

- Antibodies that often attack your body's own tissues — specifically targeting each cell's nucleus - The gold standard test for *detection of lupus*

Autoimmune Hemolytic Anemia

- Antibodies to RBC - RBC destroyed by complement mediated lysis or opsonization - *Type II hypersensitivity*

Describe type III hypersensitivity reaction in SLE.

- Arises when soluble antigen forms complexes with circulating antibody and *deposits in tissue or vessels walls and activates complement* - Immune complex—antigen-antibody (IgG) complexes activate complement, which causes tissue damage

What is the cause of Systemic Lupus Erythematosus (SLE)?

- Autoantibodies either bind directly to target auto-antigens OR form immune complexes with circulating autoantigens and then get deposited in tissues. - Immune complex deposition is the main source of injury.

What causes Sjogren Syndrome?

- Autoimmune *T-cell reaction* against an unknown self antigen expressed in these glands, or *B cell immune reactions* against the antigens of a virus that infects the glandular tissues - Promotes inflammation of exocrine gland tissues and loss of secretory cells in exocrine glands

Myasthenia Gravis

- Autoimmune neuromuscular disorder characterized by weakness of voluntary muscles - Antibodies against Ach receptors on the NMJ junction

What are the symptoms of multiple sclerosis?

- Blurry vision - Walking difficulties - Cognitive changes - Muscle weakness - Bladder dysfunction - Parathesias

What are the symptoms of SLE?

- Butterfly rash and red patches - Discoid rash - Photosensitivity - Ulcers (mouth + nose) - Serositis: pleuritis, pericarditis, and endocarditis - Renal disorders - Neurologic disorder - Accelerated atherosclerosis

Drug-Induced Lupus

- Certain drugs can cause the development of anti-nuclear antibodies. - Lupus remits after withdrawal of offending drug.

Sjogren Syndrome

- Chronic autoimmune disease in which a person's white blood cells attack their moisture-producing glands (lacrimal and salivary glands) - exocrine glands - Characterized by *dry eyes* and *dry mouth* - Also characterized by parotid/lacrimal gland enlargement

Systemic Lupus Erythematosus

- Chronic autoimmune inflammatory disease of collagen in skin, joints, and internal organs - Failure of the mechanisms that maintain self-tolerance

Autoimmune Disease

- Chronic clinical syndrome caused by the *inappropriate activation of T cells, B cells, or both against one or more bodily antigens* - Common microscopic feature: chronic inflammation without an infectious cause, leading to destruction of the tissue

Rheumatoid Arthritis (RA)

- Chronic inflammation & thickening of the synovium (membrane lining the joints) aka *pannus* - Inflammation spreads to the cartilage and erodes the bone - Characterized by joint pain and swelling

Multiple Sclerosis

- Chronic relapsing and remitting *demyelination of neurons* - *Autoreactive TH1 and TH17 cells* in CNS react to myelin antigens and secrete antigens

Microscopic Morphology of SLE

- Degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction. - IgG deposits along the dermoepidermal junction

Extractable Nuclear Antigen

- Detects the presence of autoantibodies in the blood that react with proteins in the cell nucleus. - These proteins are known as "extractable" because they can be removed from cell nuclei

What are the symptoms of myasthenia gravis?

- Diplopia and ptosis - Muscle weakness - Difficulty swallowing and chewing

Hallmarks of Sjogren Syndrome

- Dryness of body surfaces - Dry eye, mouth, skin, vagina - Keratoconjunctivitis (inflammation of the cornea and conjunctiva)

Microscopic Morphology of Hashimoto's Thyroiditis

- Excess plasma cells, macrophages, and Th1 cells form germinal centers in the thyroid gland - Infiltration by mononuclear inflammatory cells

Sclerotic Plaques

- Inflammatory lesions - Small, hard, circumscribed scars where the myelin sheath has been destroyed

Hashimoto's Thyroiditis

An autoimmune disease in which the body's own antibodies attack and destroy the cells of the thyroid gland, causing *hypothyroidism*

Describe type IV hypersensitivity reaction in multiple sclerosis.

- Myelin-specific T cells secrete cytokines ex. IL-1, IL-6, TNFα, and INFγ (vasodilation) - Allows more immune cells to enter site ex. B cells and macrophages - B cells secrete antibodies that mark myelin sheath proteins and macrophages engulf and destroy oligodendrocytes

Describe the pathophysiology of rheumatoid arthritis.

- The citrullination of proteins (ex. collagen and vimentin) causes immune cells not to recognize the proteins - Th1 in the synovium releases: IL-1, TNF, and IFN-ɣ - Th1 cells activate B cells to *produce antibodies to autoantigens ex. citrullinated proteins*

Villous Atrophy

- Total flattening of mucosal villi leading to loss of absorptive surface area - Biopsy finding of Celiac disease

Describe the pathophysiology of Hashimoto's Thyroiditis.

1. *CD8+ Cytotoxic T Cell:* killing of thyroid epithelial cells 2. *Cytokine-mediated cell death:* T cell activation leads to the production of cytokines 3. *Antibody-Dependent:* Binding of anti-thyroid antibodies, anti-thyroglobulin, and anti-thyroid peroxidase antibodies.

Describe the mechanism of celiac disease.

1. *Transglutaminase (tTG)* modifies the peptides of *gliadin (wheat protein)* so they can bind strongly to MHC class II molecules *(HLA-DQ2 or HLA-DQ8)*. 2. The bound peptide activates *gluten-specific CD4+ T cells* 3. The activated T cells can kill mucosal epithelial cells by binding Fas and can secrete IFN-γ, which activates the epithelial cell. Also induces inflammation. 4. Stimulates B cells to produce IgA antibodies against gliadin and transglutaminase. Also stimulates CD8+ T Cells that can cause tissue damage.

What are the types of autoantibodies in systemic sclerosis?

1. Anti-tropoisomerase 2. Anti-centromere

What are the three major causes of systemic sclerosis?

1. Autoimmune responses 2. Vascular damage (more vasoconstriction) 3. Collagen deposition Endothelial injury results in chronic inflammation and fibrosis.

CREST Syndrome

1. Calcinosis 2. Raynaud's 3. Esophageal dysfunction 4. Sclerodactyly 5. Telangiectasia

What is the criteria for lupus?

1. Inflammation of kidneys (nephritis) 2. Inflammation of the heart (myocarditis/pericarditis) 3. Inflammation of the lungs (pleuritis) 4. Inflammation of blood vessels (vasculitis) 5. Anemia, leukopenia, thrombocytopenia 6. Cognitive impairment, depression, memory loss

Describe the pathogenesis of systemic sclerosis.

1. Lymphocytes react against antigens in the body, and accumulate, releasing cytokines that cause *vascular injury* 2. The damaged endothelium produced less vasodilators (ex. NO), and more vasoconstrictors (ex. endothelin) 3. Vasoconstriction causes tissue *hypoxia*, which *activates fibroblasts* to produce large amounts of collagen → *fibrosis* 4. Fibrosis occurs in many organs

Which antigens are affected in multiple sclerosis?

1. Myelin basic protein 2. Proteolipid protein

Libman-Sacks Endocarditis (LSE)

A form of nonbacterial endocarditis that is seen in association with systemic lupus erythematosus

Synovial Joint

A fully moveable joint in which the synovial (joint) cavity is present between the two articulating bones

Exophthalmos

Abnormal protrusion of the eyeball

Pancytopenia

Abnormal reduction of all blood cells

Parathesias

Abnormal sensation such as burning, tingling, or numbness

Microstomia

Abnormally small mouth

Systemic Sclerosis (Scleroderma)

An immunologic disorder characterized by: - *Excessive fibrosis* in multiple tissues - Obliterative vascular disease - Evidence of autoimmunity, mainly the production of multiple autoantibodies.

What are the auto-antibodies in Sjogren's syndrome?

Anti-Ro (SSA) and Anti-La (SSB)

What are the autoantibodies in SLE?

Anti-nuclear antibodies - Autoantibodies to dsDNA - Autoantibodies to Sm - Anti-phospholipid antibodies

Anti-Phospholipid Antibodies

Antibodies against phosopholipids in SLE

Rheumatoid Factor

Antibodies to IgG produced in those with rheumatoid arthritis

Citrullination

Arginine is converted to citrulline in a protein ex. type II collagen and vimentin

HLA-DQ2 and HLA-DQ8

Associated w/ celiac disease

HLADR4

Associated with rheumatoid arthritis

What causes panytopenia in lupus?

Autoantibodies specific for red blood cells, white blood cells, and platelets opsonize these cells and promote their phagocytosis, resulting in *cytopenias*.

Discoid Rash

Chronic rash in sun-exposed areas that are plauqe-like and can scar

What causes esophagus dysfunction in scleroderma?

Collagen depositions causes absent peristalsis (dec. motility)

Peptidyl Arginine Deaminase (PAD1)

Converts arginine residues to citrulline during inflammation

Crypt Hyperplasia

Crypt elongation

Citrullinated Self-Protein

Deamination is an enzymatic, posttranslational conversion of arginine residues to citrulline residues) of joint-associated self-proteins

Enteropathy

Disease of the small intestine

Collagen Vascular Disease

Disorder that affects primarily the joints and mobility.

Telangiectasias

Distended or dilated surface blood vessels

Calcinosis

Dystrophic calcification

Goiter

Enlargement of the thyroid gland

Microscopic Morphology of Pannus

Erosion of cartilage

What causes accelerated atherosclerosis in SLE?

Immune complexes and anti-phospholipid antibodies may cause *endothelial damage* and promote atherosclerosis

What causes calcinosis in scleroderma?

Increased inflammation causes necrosis, and calcium in the cytosol bind to fragments of cell membranes and build up in the skin

Endocarditis

Inflammation of the inner lining of the heart

Lupus Nephritis

Inflammation of the kidney that is caused by systemic lupus erythematous (SLE)

Diffuse Systemic Sclerosis

Initial widespread *skin involvement*, with rapid progression & early visceral involvement.

Microscopic Morphology of Sjogren Syndrome

Intense lymphocytic and plasma cell infiltration with ductal epithelial damage in a salivary gland.

Myelin Basic Protein

Major component of myelin that can be detected in the cerebrospinal fluid of people with multiple sclerosis

Celiac Disease

Malabsorption syndrome caused by an *immune reaction to gluten*

Transglutaminase

Modifies gliadin proteins so that they bind strongly to HLA-DQ2, which can activate antigen specific T4 cells

Malar Rash

Red macular lesions distributed over the forehead, cheeks, and chin, resembling the pattern of a butterfly

Discoid Lupus

Red to pink papules and plaques of face, scalp, ear canal, follicular plugging, eventual atrophic scarring

Antinuclear Antibodies (ANA) Assays

Tests for antinuclear antibodies in the blood

Sclerodactyly

Thickening and tightening of the skin on the fingers and hands

Thymoma

Tumor of the thymus gland

Myasthenia gravis is an example of which type of hyperactivity?

Type II

Rheumatoid arthritis is an example of which type of hypersensitivity?

Type III

SLE is a major example of what type of hypersensitivity?

Type III

Multiple sclerosis is an example of which type of hypersensitivity?

Type IV