Autoimmune Diseases + Misc

Most common monomorphic and polymorphisms in immunoregulatory genes

Most common monomorphic and polymorphisms in immunoregulatory genes

monomorphic: AIRE, FOXP3, FAS/FASL

polymorphic: CD25 (IL-2 alpha chain), IL-10, CTLA-4

Autoimmune Hemolytic Anemia

Hypersensitivity Type: cytotoxic type II (organ)

 

Mechanism: Ab against RBCs, either via opsonization for phagocytosis (extravascular) or complement activation for lysis (intravascular)

• Cold Agglutinin Disease = IgM Ab, react at <37*C

• Warm Ab Hemolytic Anemia = IgG Ab, react at >37*C

   

Other: increased lymphocytosis + autoimmune cytopenia = signs of Autoimmune Lymphoproliferative Syndrome (ALPS)

ID via Coombs test —> detect Ab on the RBCs

 

HLA association? no

Goodpasture Syndrome

Hypersensitivity Type: cytotoxic type II (organ)

 

Mechanism: IgG against type IV collagen induces antibody dependent cellular cytotoxicity (ADCC) —> destroys pulm alveoli and glomerular basement membrane

 

Symptoms: fatigue, naus/vom, resp distress, hemoptysis, hematuria, HTN, urination discomfort, edema

- linear/smooth pattern on immunofluorescence of kidney biopsy

 

HLA association? no

Hashimoto’s Thyroiditis

Hypersensitivity Type: cytotoxic type II and type IV (organ)

 

Mechanism:

• Type II: Ab against thyroid cells/Tg/TPO —> necrosis/apopt.

• Type IV: Th1 and Th17 mediated inflammation, increase IL-23, attacks thyroid cells —> apopt.

 

Symptoms: hypothyroidism = cold sensitivity, high TSH, low T4, fatigue, weight gain, alopecia, goiter, increased risk of non-hodgkin’s lymphoma

 

HLA association? Yes DR3

Graves’ Disease

Hypersensitivity Type: non-cytotoxic type II, agonistic (organ)

 

Mechanism: IgG acts as anti-TSH receptor —> thyrotoxicosis (TSH receptor constituatively stimulated)

 

Symptoms: hyperthyroidism = heat intolerance, goiter, low TSH, high T3/T4, weight loss, opthalmopathy,

 

HLA association? no

Myasthenia Gravis

Hypersensitivity Type: non-cytotoxic type II, antagonistic (organ)

 

Mechanism: anti-AChR Ab —> bind AChR and trigger internalization of the receptors and degredation —> unable to have neuromusc. signaling

 

Symptoms: chronic musc. fatigue, weakness, ptosis, diplopia, worsens w/ musc. use, improves w/ ACh esterase inhibition

 

HLA association? no

LSE w/ Lupus Nephritis

Hypersensitivity Type: type III (systemic)

 

Mechanism: Tcell dependent Ab response to self-Ag (RNA, DNA, nuclear proteins, etc.)

 

Symptoms: butterfly rash, photo-sensitivity, arthritis, arthralgia, myositis, aseptic fever, lymphadenopathy, hepatosplenomegaly, fatigue, Raynauds, cytopenia, etc

 

HLA association?

Ankylosing Spondylitis

Hypersensitivity Type: type III (systemic)

 

Mechanism: idk but it’s male predom.

 

Symptoms:

• Early: sacroiliitis —> pain/stiffness in lower back + hips, esp after periods of inactivity

• Eventually: fusion of vertebae restricts movement, can progress to other joints too

• May have uveitis and photophobia

• tx w/ TNF-a inhib.

 

HLA association? YES HLA-B27

Rheumatoid Arthritis

Hypersensitivity Type: type III and type IV (systemic)

 

Mechanism: anti-CCP and rheumatoid factor (IgM against IgG)

 

Symptoms: pain + stiffness in mult. joints (esp. hands/wrists/knees) that’s worse following extended inactivity, can cause non-hemolytic anemia from the systemic uveitis and inflamm.

 

HLA association? yes

T1DM

Hypersensitivity Type: type IV, endocrine (organ)

 

Mechanism: Th17 + Th1 mediated inflamm recruitment —> diffuse damage of pancreatic islet cells. Also autoreactive CTLs target beta-cells

• +85% have Abs against insulin, glutamic acid decarboxylase, and/or other islet cell Ags

 

Symptoms: polydipsia, polyuria, polyphagia, ketoacidosis. Frequently comorbid w/ thyroid disease

 

HLA association? Yes! DQ2! Also CD25 & CTLA4 polymorphisms

Addison’s Disease

Hypersensitivity Type: type IV, endocrine (organ)

 

Mechanism: Th1 mediated destruction of adrenal cortex, often w/ Ab involvement

 

Symptoms:

• skin + mucosal hyperpigmentation from high MSH

• no cortisol —> metabolic acidosis

• no aldosterone —> hypotension (salt wasting) and hyperkalemia [Fuller is a dumb ass and said those sx are due to no cortisol >:/…]

• Ab against 21-hydroxylase

 

HLA association? yes

Multiple Sclerosis

Hypersensitivity Type: type IV, CNS (systemic)

 

Mechanism: autoreactive Tcells promote infiltration and assumed IgG in the CSF against myelin basic protein —> progressive demyelination of CNS

 

Symptoms: limb weakness, spasticity, sensory loss, diplopia and/or blurred vision, ataxia, bladder dysfunction, fatigue, facial weakness resembling Bell’s Palsy, paralysis

**consider how these sx could resemble late stage tertiary syphilis

 

HLA association? yes

Celiac Disease

Hypersensitivity Type: type IV, GI

 

Mechanism: Th1 mediated destruction of gut epithelium with Abs generated (anti-tissue transglutaminase Ab)

• Gliadin (from gluten) = allergen

• transglutaminase is the auto-Ag that modifies the gliadin peptide

• innate and adaptive immune responses

 

Symptoms: persistent diarrhea, weight loss/malabsorption, abdom distention, damage mainly to small intestine

• often comorbid w/ T1DM, thyroid disease,CVID, or Selective IgA defic (would cause false neg on celiac Ab test)

• can also result in extraintestinal sx: neuro, msk, etc

 

HLA association? yes

Celiac vs Gluten-Intolerance

Crohn’s Disease

Hypersensitivity Type: type IV, GI

 

Mechanism: Th1 and Th17 mediated cytokines affecting GI tract, most commonly the ileum, uncontrolled activation of immune cells

 

Symptoms: persistent diarrhea, urgent need to defecate, LRQ abdom cramping, non-bloody diarrhea, weight loss, cobblestone mucosa, non-caseating granulomas, discontinuous patchy inflamm/lesions

• Increased risk for primary sclerosing cholangitis and colorectal cancer

 

HLA association?

Compare Crohn’s vs Ulcerative Colitis

C. Diff major characteristics

• assoc w/ Abx use

• massive watery diarrhea, fecal leukocyte (+)

• pseudomembrane formation (white/yellow plaques)

• mucosal ulcerations, fibrin, inflamm cells

• dx via Toxin A & B in stool

How to TNF treatments work for autoimmune diseases?

bind to TNF specifically or provide receptor mimic to decrease inflammation

Psoriasis (vulgaris/plaque subtype most common)

Hypersensitivity Type: type IV, integumentary

 

Mechanism: cytokine dysregulation —> skin cells rise to the surface too fast

 

Symptoms: red, scaly, well-defined, silvery-white, dry plaques, preferentially on elbows/knees/scalp/lumbar area. Plaques can be erythematous and pruritic.

• often comorbid w/ psoriatic arthritis, Crohn’s, psych disorders, and uveitis

 

HLA association?

APECED aka APS type I

(systemic)

 

Mechanism: defective AIRE —> impaired thymic (-) selection & Treg induction —> increased autoimmune disease

 

Symptoms: chronic mucocutaneus candidiasis (infancy), Ab against IL-17, hypoparathyroidism (before 10 yr) , adrenal failure (~15 yr)

 

HLA association? no

IPEX Syndrome

(systemic) X-linked

 

Mechanism: defective FOXP3 —> impaired immune regulation in the periphery —> increased autoimmune disease

 

Symptoms: presents w/in 1st days of life w/ severe enteropathy: chronic watery/mucoid/bloody diarrhea that’s typically unresponsive to dietary exclusions or bowel rest —> malabsorption and failure to thrive

• endocrine: neonatal T1DM, thryoiditis (hypothyroidism most common)

• skin: from mild dermatitis to severe diffuse erythematous exudative plaques that evolve to lichenification

• excessive lymphoprolif. (hepatosplenomegagly, lymphadenopathy)

• autoimmune cytopenia

• kidney disease

 

HLA association? no