Autoimmunities

Question 1

Insulin-Dependent Diabetes Mellitus

Answer 1

Type: Type IV T-cell mediated

Cause: This disease is mediated by CTLs that have specificity for some determinant(s) in beta pancreatic cells in the islets of Langerhans.

Result: Beta cells are destroyed and no longer produce insulin. They cannot regenerate, and there is a finite number.

Symptoms: Heaps, but if left untreated, can lead to coma and death.

Tissue sample: You’ll see mass infiltration of lymphocytes (mostly CTLs) into islets of Langerhans

Treatment: Daily insulin replacement

Question 2

Grave’s Disease

Answer 2

Type: Type II Antibody Mediated

Cause: Thyroid-stimulating hormone receptor-specific IgG antibodies cause over-production of thyroid hormone because these antibodies serve as receptor agonists - they mimic TSH.

Symptoms: bulging eye syndrome, enlarge thyroid, heat intolerance, nervousness, irritability, weight loss, and moist skin

Long-term Issue: Recall that a mother passes her IgG antibodies to her fetus. A pregnant woman with this condition will pass the IgGs to the developing fetus, and the fetus will also suffer from the condition. Upon birth, the child will receive plasma exchange to restore normal thyroid function

Question 2

Multiple Sclerosis

Answer 2

Type: Type IV T-cell mediated

Cause: Auto-reactive Th1 CD4+ effector cells lose tolerance for determinants of the myelin sheath around nerve cells. The Th1 cells activate macrophages; macrophages produce inflammatory cytokines. The inflammatory response causes demyelination of white matter in the CNS.

Result: poor transmission of nerve impulses Symptoms: progressive muscle weakness, impaired vision, loss of coordination, and spasticity

Diagnosis: test for oligoclonal bands of IgG in the CSF

Treatment: immunosuppressive drugs and IFN-B1

Question 3

Pemphigus vulgaris

Answer 3

Type: Type II Antibody Mediated

Cause: An IgG-mediated response specific for desmoglein 1 and 3 Result: loss of cohesion in keratinocytes

Symptoms: painful chronic blistering of skin

Diagnosis: punch biopsy of lesion followed by immunofluorescent staining to ID IgG4 bound to tissue

Treatment: corticosteroids and anti-inflammatory drugs

Question 4

Point mutation that alters the amino acid at position 57 of the HLA-DQ beta chain has a strong association with?

Answer 4

The development of type I diabetes mellitus

Question 4

What is rheumatoid factor?

Answer 4

It is an immunoglobulin made by 80% of patients who have rheumatoid arthritis. It is IgG, IgM, and IgA that have specificity for Fc regions of human Ab. The patient is making Ab that bind to the patient’s own Ab.

Question 5

Rheumatoid Arthritis

Answer 5

Type: Type IV T-cell mediated

Cause: Auto-reactive T-cells produce an inflammatory response in the joints, causing damage to the soft tissues (cartilage and ligaments).

Result: loss of function and disfigurement of the joints.

Epidemiology: 1-3% of US population; women:men = 3:1.

Treatment: infliximab and rutiximab (KNOW THIS)

Question 6

Autoimmune Hemolytic Anemia

Answer 6

Type: Type II Antibody Mediated

Cause: IgG and IgM antibodies acquire a response to surface determinants of RBCs. They bind to RBCs and become ligands for complement component C1q, activating the classical cascade. Activation results in formation of MAC complexes and of deposition of C3b on RBCs. Opsonized RBCs are taken and destroyed by phagocytes that recognize complement and IgG opsonins.

Symptoms: anemia

Diagnosis: direct Coomb’s Assay

Treatment: Corticosteroids

Question 6

Your 65 y/o patient comes into the office complaining of being tired and having double vision. You note on physical exam that he is suffering from ptosis (drooping eyelids). What is your preliminary diagnosis, and how do you treat it?

Answer 6

Myasthenia gravis, treated with a cholinesterase inhibitors - pyridostigmine.

Myasthenia is not a painful condition - this is a way to distinguish it from the other nerve conditions in this group.

Question 7

Miller-Fisher Syndrome

Answer 7

This is a less common form of Guillan-Barre that descends from the facial muscles down to the trunk and limb.

The same result occurs without treatment; this disease is no worse than Guillan-Barre.

Very rapid progression.

Causes demyelination.

Question 8

A Graves disease sufferer is prego. Is the fetus going to be born with Graves?

Answer 8

Sho is.

But ain no big thang - just give it a plasma exchange!

Question 9

Myasthenia gravis

Answer 9

Type: Type II Antibody Mediated

Cause: IgG-mediated response to acetylcholine receptors on muscle cells interferes with/antagonizes normal signaling at the NMJ. When these antibodies bind the acetylcholine receptors, the receptors are endocytosed and destroyed.

Result: Depletion of acetylcholine receptors at NMJ, making muscles less sensitive to neuronal stimulation.

Symptoms: Initially, ptosis and diplopia (double vision), then progression to generalized muscle weakness

Treatment: anti-inflammatory drugs and cholinesterase inhibitor to prevent degradation of acetylcholine. Does NOT cause demyelination.

Question 10

For several years, your 8 y/0 patient has experienced progressive muscle weakness and loss of coordination. His leg muscles have become rigid and painful (hypertonia). What immunological effector is responsible for his condition? What disease is this?

Answer 10

Th1 cells specific for myelin sheath determinant Multiple sclerosis

Question 12

Autoimmune (Idiopathic) Thrombocytopenic Purpura

Answer 12

Type: Type II Antibody Mediated

Cause: 2 targets:

1) IgG binds to and inhibits the enzyme that cleaves von Wildebrand factor. When vWF is not cleaved, excessive platelet adhesion occurs, partially occluding small blood vessels so that when RBCs travel through, they are damaged (this is called microangioplastic hemolytic anemia); and
2) IgG can be specific for a surface integrin of platelets called Gp2b/3a) In addition, excessive platelet adhesion leads to an overall reduction of platelet number, so patients develop purport.

Symptoms: microangioplastic hemolytic anemia, thrombocytopenia (low platelet count), purpura, damage in kidneys, liver, and brain due to excessive platelet adhesion, and reduced platelet numbers

Diagnosis: observation of microangioplastic hemolytic anemia

Treatment: Plasma exchange with healthy donor

Question 13

All autoimmune diseases are more likely to happen after ________________

Answer 13

an infection. Other than that, your body should not be able to mount an immune response against self determinants.

Question 14

Sjogren’s Syndrome

Answer 14

Type: Type IV T-cell mediated

Cause: Auto-reactive T-cells are specific for determinants expressed in the exocrine glands that produce tears and saliva. Other affected tissues can include kidneys, blood vessels, liver, and brain.

Symptoms: dry eyes, mouth, nose, skin, and vag; sometimes tooth decay due to lack of saliva

Epidemiology: 2nd most common rheumatic disease; men:women = 1:9

Diagnosis: Schirmer test to measure tear production and measurement of anti-nuclear antibody titers Anti SSA (Ro) and Anti SSB (La) (KNOW SCHIRMERS)

Treatment: artificial tears, punctal plugs, and goggles.

Question 15

A 21-yr old female complains that her fingers and knees have been becoming increasingly achy over the past year and half. Blood work reveals an anti-dsDNA titer of 512. What additional clinical findings do you expect?

Answer 15

Reduced kidney function caused by immune complex deposition in the kidney.

Blood in urine; protein as well High titers of anti-histone ABs and anti-ribosome ABs

Positive direct Coomb’s test because many develop autoimmune hemolytic anemia

Reduced complement C1 levels (C1 most commonly measured)

Question 17

Scleroderma

Answer 17

Type: Type II Antibody Mediated

Cause: IgG-mediated response causes damage to vascular endothelium of arteriole and smooth muscle cells that results in replacement of damaged tissue with collagen, and eventually, skin hardening and thickening.

Result: Skin damage, as well as damage to kidneys, blood vessels, liver, and brain

Diagnosis: presence of anti-nuclear Ab, anti-topoisomerase Ab, and anti-centromere Ab

Treatment: Nothing standard

Question 18

Mixed Essential Cryoglobulinemia

Answer 18

Type: Type III Antibody Mediated

Cause: Cryoglobulins are immunoglobulins that become insoluble at reduced temperature. They are usually produced by patients that have a B-cell proliferative disorder. They bind to the Fc regions of antibody molecules, causing an immune complex disorder.

Symptoms: Meltzer’s Triad: purpura, arthralgia (joint pain), and myalgia (muscle pain) Be familiar with Bence-Jones proteins, a way to describe the composition of some cryoglobulins that have only a light chain.

Question 18

Systemic Lupus Erythematosus

Answer 18

Type: Type III Antibody Mediated

Cause: An IgG autoantibody response specific for self macromolecules, including dsDNA, histones, and ribosomes. These autoantibodies bind to surface determinants, initiating inflammatory responses that lead to tissue damage and release of autoantigens. Immune complexes are formed, resulting in an immune complex disease.

Result: progressive disease that leads to vasculitis, kidney damage progressing to glomerulonephritis, and neurological dysfunction.

Symptoms: fever, malaise, joint pain, myalgia, and fatigue. Progressive kidney dysfunction due to the deposition of immune complexes and resulting inflammation.

Treatment: anti-inflammatory drugs

Question 19

Immunologically Privileged Sites

Answer 19

Eyes, testes, and placenta During development of immune system, no elimination of self-reactive T-cells to determinants of those locations occurred, so if a person is injured, and one such determinant is released into the bloodstream, a response can be generated. The T-cells will then return to that site of injury and carry out a response against the “determinant”.

Question 20

The difference between an agonist antibody and an antagonist antibody?

Answer 20

Over-production vs. under-production respectively of normal result of ligand binding.

Question 22

Subacute Bacterial Endocarditis

Answer 22

Type: Type III Antibody-Mediated

Cause: Streptococcus viridans can colonize heart valves if they become damaged. IgG antibodies specific for S. viridans determinants bind to the bacteria, promoting recognition of the immune complex by phagocytes and the initiation of the classical complement cascade.

Result: inflammation due to the immune response causes further damage to heart valves and myocardium.

Question 23

Your previously healthy patient presents with bulging eyes with little eye movement and complains of numerous symptoms including unexplained weight loss, nervousness, and irritability. On physical exam, you note that her thyroid is enlarged. What clinical finding do you expect in this case?

Answer 23

Anti-TSHR (thyroid-stimulating hormone receptor) Abs

Question 25

Molecular Mimicry

Answer 25

Occurs when a determinant of a microorganism is similar enough to a host determinant that when the host generates an immune response against the pathogen, the antibodies that have specificity for some of the pathogen’s determinants cross-react with host determinants.

Question 26

Goodpasture’s Syndrome

Answer 26

Type: Type II Antibody Mediated

Cause: IgG response to type-IV collagen, which lines the basement membranes body-wide). Antibodies bind the collagen, initiating an inflammatory response mediated by the classical complement cascade and by macrophages that cause tissue damage.

Result: Tissue damage, especially in the kidneys, which culminates into glomerulonephritis

Symptoms: loss of appetite, weakness, fatigue, progressive loss of kidney function

Diagnosis: measure glomerular basement membrane-specific antibodies (Anti-GMB Abs) - a sub-type of IgG4

Treatment: plasma exchange or anti-inflammatory drugs

Question 27

Guillain Barre Syndrome

Answer 27

Type: Type II Antibody-mediated/molecular mimicry

Cause: This disease results from production of an IgG response during infection (usually Campylobacter). IgG made in response to the bacterial infection cross-reacts with gangliosides.

Result: Demyelination

Symptoms: Symmetrical weakness of lower limbs, rapidly ascending to upper limbs and face with difficulty swallowing and breathing. Partial paralysis often occurs, but in most cases can be reversed with treatment.

Treatment: plasma exchange and immunosuppressants. The above-described course of symptoms is a notable feature of this disease. If treated soon enough, patients can recover, but if not, patients can become totally paralyzed in a matter of weeks.

Very rapid progression! Causes demyelination

Question 28

Wegener’s Granulomatosis

Answer 28

Type: Type II Antibody-medatied/molecular mimicry

Cause: This condition is mediated by antibodies generated in response to either viral or bacterial infection that cross-reacts with neutrophil determinants. IgG ANCAs (anti-neutrophil cytoplasmic antibodies) bind to their determinants on the surface of neutrophils, causing the neutrophils to increase adhesion molecule expression, resulting in their increased binding to vascular endothelial cells. They then release their inflammatory mediators, causing damage to the vasculature.

Symptoms: first rhinitis, conjunctivitis, and lung infiltrates, followed by rapidly progressive kidney dysfunction leading to glomerulonephritis. Granulomas are usually found in all infected tissues.

Treatment: plasma exchange and anti-inflammatory drug treatment

Question 29

Acute Rheumatic Fever

Answer 29

Type: Type II Antibody Mediated

Cause: A normal IgG response to GAS reacts with normal host tissue because some streptococcal envelope components are very similar to determinants expressed on cardiac tissue (this is called molecular mimicry)

Result: Myocarditis and heart valve scarring

Symptoms: chest pain, SOB, fever, and joint pain

LONG TERM PROBLEM: A person who gets acute rheumatic fever is more likely to develop subacute bacterial endocarditis.