Chapter 11 - Organ Autoimmunity

Myasthenia Gravis Principle

Affects neuromuscular junction; skeletal muscles most affected

Causes weakness and muscle fatigue

Myasthenia Gravis Cause

Antibody-mediated destruction of acetylcholine receptor at post-synaptic membrane of neuromuscular junction

• acetylcholine released by neuron fails to initiate a signal

Myasthenia Gravis Symptomsdr

Weakness; Easily fatigued - worsens with exercise and improves with rest

Double vision

Difficulty climbing stairs

Systemic - trouble talking and walking; respiratory failure due to muscle weakness; life threatening

Localized - isolated eye abnormalities diagnosed w/ ocular myasthenia gravis; droopy eyelids

Myasthenia Gravis Autoantibodies

Autoantibodies Against:

• Acetylcholine (nicotinic) Receptors - present in >80% of cases

• Tyrosine Kinase (muscle-specific receptors)

  • may be present in patients who don’t have acetylcholine receptor autoantibodies

Celiac Disease Principle

Inability to digest gluten; Intolerance to dietary gluten - protein in wheat, barley, and rye

Inflammation of the small intestine leads to poor absorption of nutrients

Risk - Women at highest risk; first degree relatives with celiac’s; Caucasians of western Europe

Celiac Disease Autoantibodies

Gliadin - component of gluten

Autoantibodies Against:

• Tissue Transglutaminase (TTG-IgA) - enzyme that deaminates (removes amine) the gliadin component of gluten; unable to deaminate = inability to digest

• Endomysium (EMA-IgA) component of connective tissue lining smooth muscle within the intestine

Pernicious Anemia Principle

Results from B12 (cobalamin) deficiency (inability to absorb B12); B12 made by colonic bacteria

Intrinsic Factor

• binds to B12 after it is made by colonic bacteria

• travels to terminal point of the ileum

• receptors to complex (Intrinsic Factor-Cobalamin Complex) allow B12 to enter circulation

Pernicious Anemia Autoantibodies

Autoantibodies Against:

• Intrinsic Factor - lowers levels of intrinsic factor or block binding of complex to receptor in terminal ileum

• Gastric Parietal Cells - results in chronic gastritis

Premature Ovarian Failure

Rare

Diagnosis before age 40

• autoantibodies against estrogen producing cells

• estrogen deficiency

Young age diagnosis - delayed puberty, amenorrhea (no periods), infertility, osteoporosis

Cells in Testis

Leydig Cells - synthesize testosterone

Sertoli Cells - involved in sperm production

Autoimmune Testicular Failure

Low testosterone and infertility

Autoantibodies against:

• Steroid Cells - Affect Leydig cells = decreased testosterone = low sperm count

• Sperm

  • IgA or IgG subclasses of antibodies

  • Testicular trauma or vasectomy can cause anti-sperm antibodies develop as a result of compromised testes (testes - immunologically privileged site)

Adrenal Cortex

Cortisol - secreted in stress response; glucocorticoid

Aldosterone - regulates fluid / electrolyte; mineralocorticoid

Adrenal Medulla

Catecholamines - secreted in response to the sympathetic nervous system

Addison’s Disease / Primary Adrenal Insufficiency Principle

Autoimmune destruction of the cortex; fatal outcomes

• Aldosterone and cortisol deficiency

• gland will not respond to physiological stress

Prevalence

• 1:10,000 people; equal in men and women

• Women are more likely to have T1DM and Addison’s

• Rate of autoimmune adrenal failure = 0.5% in patients with T1DM

Addison’s Disease Signs and Symptoms

Hyperpigmentation - hallmark sign

• overexpression of melanocyte-stimulating hormone

  • part of the pre-prohormone secreted when pituitary adrenocorticotropin hormone (ACTH) increases to stimulate the adrenal cortex to produce cortisol

• Cortisol and aldosterone deficiency

• Sodium and water loss in urine

  • low blood pressure, dehydration, and low blood sugar

  • shock and death

• Fatigue, weakness, salt craving, anorexia, weight loss, growth failure (in children)

Addison’s Disease Autoantibodies

Autoantibodies Against:

• Adrenal Cortex - detected by IFA

• 21-hydroxylase Enzyme - detected by radio binding or immunoadsorption assay

If high risk, patient tested prior to onset of disease

Addison’s Disease Treatment

Hormone Replacement - lifelong; glucocorticoids and mineralocorticoids

Hydrocortisone Replacement - stress dose

Pancrease

Secretes digestive enzymes and hormones

Islets of Langerhans produce hormones

• Beta - secrete insulin

• alpha - secrete glucagon

• delta - secrete somatostatin

Type 1 Diabetes Mellitus Principles

Uncontrolled hyperglycemia - elevated blood sugar

Autoimmune disease of endocrine pancreas - Beta-Cells of islet destroyed = decreased insulin secretions

Type 1 Diabetes Mellitus Signs

Increased: thirst, hunger, weigh loss

Increased urination from high blood sugar - excreting high amounts of glucose attracts water (h2o follows solutes)

Develops over a period of weeks to months

Type 1 Diabetes Mellitus Autoantibodies

Autoantibodies Against:

• Proteins within the pancreatic Beta cells

  • Glutamic acid decarboxylase-65 (GAD-65)

  • Insulin-associated antigen

  • Insulin itself

Autoantibodies may circulate for years prior to diagnosis

Type, number, and titer predict the likelihood of developing clinical disease

Type 1 Diabetes Mellitus Lab Results

Elevated serum blood glucose levels

Increased urine blood glucose

Elevated serum ketones

• breakdown of fatty acids as an alternative energy source (due to inability to use glucose as energy, body will use fat)

• Ketones will enter urine when case is severe

  • Lab will test serum and urine ketones to determine severity

Graves Disease Principles

Autoimmune Hyperthyroiditis

Medicated by thyroid stimulating immunoglobulin (TSI)

• autoantibody TSI binds to TSH receptor on thyroid follicular cells

• stimulates thyroid hormone release

  • independent of TSH - results in significantly elevated hormone production

Grave’s Disease Lab Results

Antibodies elevated but not specific for graves disease

• antithyroglobulin and antithyroid peroxidase

Assay - indirect immunofluorescence assay, ELISA, or immunoprecipitation assay

Grave’s Disease Signs and Symptoms

Goiter

Rapid heart rate, increased blood pressure

Weight loss

Muscle Weakness, brisk reflexes

Difficulty concentrating

Exophthalmos - stare and bulging eyes

Anxiety, tremor, restlessness

Difficulty sleeping, heat intolerance

Graves Disease Treatment

Drugs to block thyroid function, control high blood pressure, and high heart rate

Surgery

• resecting the thyroid but not the parathyroid

• Radio blasting with ¹³¹Iodine followed by hormone replacement

Hashimoto’s Thyroiditis Principle

Autoimmune Hypothyroidism

CD4 T-helper cells react to a specific thyroid antigen

CD4 recruits CD8 cytotoxic cells that attack and destroy gland tissue

Hashimoto’s Thyroiditis Lab Results

Elevated TSH

Low thyroid hormone (thyroxine) or normal (if compensated)

Hashimoto’s Thyroiditis Autoantibodies

Autoantibodies Against:

• anti-thyroglobulin

• anti-thyroid peroxidase - inhibits enzyme function in vitro

Hashimoto’s Thyroiditis Signs + Symptoms

Enlarged thyroid gland (goiter) - attempted compensation by making the “factory” larger to produce more thyroid hormone

Low energy levels, weight gain

Dry skin

Cold intolerance

Apathy

Bradycardia

Thyroid

Shield-shaped organ in front of neck

Follicles produce thyroid hormone

• T3 and T4 (thyroxine)

  • stimulated by TSH - thyroid stimulating hormone made by pituitary

    • Pituitary → TSH → Thyroid → makes T3 and T4 with tyrosine

Thyroperoxidase

Essential enzyme that oxidizes iodine prior to linking to thyroglobulin

11% have autoantibodies against it; middle aged women increase about 25%

Thyroid Hormone

All cells have a nuclear receptor for thyroid hormone

Essential for multiple cellular functions

• neuron development

• bone metablosims

• normal linear growth

• muscle contractability

• basal metabolic rate