First Aid, Chapter 8, Immunologic Disorders, Immune Endocrinopathies (Thyroid, Diabetes, and Adrenal), and Immune Renal Disease

Question 1

What antibodies are found in Grave’s disease? What cells are involved?

Answer 1

Immune Mechanisms—Antibodies to thyryoid-stimulating hormone (TSH) receptor that stimulate the thyroid gland, are specific for the disease. Thyroid peroxidase and thyroglobulin antibodies are frequently found, but they are not disease-specific. B lymphocytes and CD4 and CD8 T lymphocytes are involved (i.e., intrathyroid T lymphocytes with B lymphocytes organized in germinal centers), and Th2 cells are primarily responsible for the disease.

Question 2

What are the clinical features of Grave’s disease? What is the female to male ratio?

Answer 2

—Hyperthyroidism (palpitations, tremor, heat intolerance, sweating, anxiety, emotional lability, weight loss with increased appetite) with diffusely enlarged goiter and exophthalmopathy as well as pretibial myxedema may occur. The disease occurs more often in women than men, with a ratio of 7:1.

Question 3

What is the genetic association of Grave’s disease?

Answer 3

Monozygotic twins 20–40%

10% occurrence in siblings

HLA-DR3 (whites)

CTLA-4 alleles

HLA-DR expression by thyroid epithelium

Question 4

How many patients with Grave’s will relapse and what is a predictor of relapse?

Answer 4

Fifty percent of patients with hyperthyroid Graves’ disease will relapse after 1 year of treatment with antithyroid drugs. The level of autoantibody to TSH receptor is a useful predictor for relapse and remission.

Question 5

What are the antibodies in Hashimoto’s throiditis? What are the immune mechanisms/cells involved? Describe differences in the epithelial cells.

Answer 5

Immune Mechanisms—Antibodies exist for thyroid peroxidase and thyroglobulin, as well as TSH receptor, correlating with lymphocyte infiltration and decrease with treatment. Immune mechanisms involved include IgG1/IgG3 complement fixation. There is FAS expression on the thyroid with cytotoxic destruction. Thyroid germinal centers with antibody production are noticed. Epithelial cells are enlarged with distinctive eosinophilic cytoplasm due to increased mitochondria (Hürthle cells).

Question 6

What are clinical features of Hashimoto’s? What age does it affect? What is the femail to male predominance?

Answer 6

Clinical Features—Patient usually presents with an atrophic thyroid but may have goiter. The disease is defined by chronic progressive autoimmune thyroiditis. Clinical features of hypothyroidism (fatigue, weakness, cold intolerance, weight gain, constipation, dry skin, depression, growth failure, delayed puberty). Prevalence increases with age, with more women afflicted than men (7:1).

Question 7

What is the genetic association of Hashimoto’s thyroiditis?

Answer 7

Monozygotic twins 30–60%, HLA-DR3 and CTLA-4 are often involved.

Question 8

How is Hashimoto’s thyroiditis diagnosed?

Answer 8

Most hypothyroid patients are thought to have Hashimoto’s disease, although thyroid antibodies are sent for confirmation. High-titer thyroid Abs are present, with clinical presentation of pyogenic thyroiditis that is characterized by thyroid area pain and fever. Other causes of thyroiditis (postpartum, acute, subacute, and silent) need to be ruled out.

Question 9

What is the function of AIRE?

Answer 9

AIRE is a transcription factor expressed in medullary thymic epithelial cells that is responsible for the expression of antigens found elsewhere in the body, and thus guides T-cell–negative selection.

Question 10

Which of the following glands is not involved in APS-2: adrenal, thyroid, parathyroid, or gonads?

Answer 10

parathyroid

Question 11

What chromosome does genetic mutation of the AIRE gene occur on in APS-1?

Answer 11

21q22.3

Question 12

What are the manifestations of APECED or APS-1?

Answer 12

mucocutaneous candidiasis of the mouth and nails (this is postulated to be mediated by anti- IL17 or IL-22 antibodies), hypoparathyroidism, and autoimmune adrenal insufficiency. Usually, the disease first manifests in childhood, and the patient then develops these three diseases in the first 20 years of life. The other autoimmune endocrinopathies include:

GI disease  
Chronic hepatitis  
Autoimmune skin disorders  
Ectodermal dystrophy  
Keratoconjunctivitis  
Immunologic defects  
Asplenia  
Cholelithiasis  
Mucosal cancer

Question 13

In APS-1, what antibodies is the mucocutaneous candidiasis of the mouth and nails mediated by?

Answer 13

anti- IL17 or IL-22 antibodies

Question 14

How does autoreactivity start in APS-1?

Answer 14

In this pathology, autoreactive T cells in the thymus escape negative selection by not being exposed to self-antigen in the thymus

Question 15

What antibodies form in APS-1? What organs do they affect? Which glands do they spare? What gender does it affect more?

Answer 15

Antibodies are formed to 21-hydroxylase (adrenal), IL-17 and IL-22 (candidiasis), islet cells (DM), IFNω. Autoantibody to calcium-sensing receptor, CYP1A1, CYP17, CYP21 A2, and tryptophan hydroxylase could also be present. Autoimmunity affects parathyroid (onset in 20s) > adrenal > gonadal > gut. APS-1 does not usually involve DM or the pituitary gland. Affects women more than men.

Question 16

How is diagnosis of APS-1 made?

Answer 16

Diagnosis is made by having any two autoimmune conditions, or one autoimmune condition plus a mutation in the AIRE gene.

Question 17

Is APS-1 or APS-2 more common?

Answer 17

APS-2

Question 18

What is the female:male ratio of APS-2?

Answer 18

3:1

Question 19

What are the most commonly affected glands in APS-2?

Answer 19

Adrenal > type I diabetes = thyroid > gonadal.

Question 20

What conditions is APS-2 associated with?

Answer 20

Celiac disease 
Vitiligo  
Pernicious anemia 
Myasthenia gravis 
Stiff-person syndrome 
Alopecia  
Sjögren’s syndrome  
Antiphospholipid antibodies
Rheumatoid arthritis

Question 21

What are the autantibodies in APS-2?

Answer 21

Autoantibodies are to cytochrome enzymes, which include CYP21A2, CYP17, and CYP11A1. Antibodies to 21-hydroxylase, tissue transglutaminase (IgA) may be present.

Question 22

What are the genetics of APS-2?

Answer 22

Fifty-percent familial (autosomal dominant and polygenic recessive) and HLA DRB0404. CTLA-4 gene polymorphism is associated with APS-2 component disorders. APS-2 is commonly diagnosed between 20 and 40 years of age.

Question 23

What are the clinical features of IPEX?

Answer 23

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a form of autoimmune enteropathy. This life-threatening disorder typically presents during infancy and is characterized by dermatitis, intractable diarrhea, and recurrent infections, and is associated with autoimmune endocrinopathy.

Clinical Features—Dermatitis is a key feature of this condition. Diarrhea is severe and a biopsy of the small bowel shows partial or complete villous atrophy, a mononuclear cell infiltration in the lamina propria, and increased expression of MHC class II antigens. This autoimmune disease is diverse and includes:

Insulin-dependent diabetes often at infancy
Membranous glomerulonephritis
Autoimmune cytopenias: Hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), autoimmune neutropenia
Autoimmune hepatitis
Hypothyroidism
50% of patients have antienterocyte antibodies.

Question 24

What are the genetics of IPEX?

Answer 24

Maps to the X-chromosome in the region of the WAS gene (WiskottAldrich), but is distinct from that gene—Xp11.23-Xq21.1. FOXP3 is a transcription factor responsible for the production of T regulatory cells inside the thymus. Mutation of FOXP3 results in depletion of Tregs. CD25 (IPEX-like syndrome) and STAT5B (autosomal recessive) mutations can also cause an IPEX-like presentation.

Question 25

What is the treatment for IPEX?

Answer 25

Without early recognition and treatment, children with IPEX usually die in the first 2 years of life from sepsis or failure to thrive. Treatment of IPEX involves bone marrow transplant. There has also been clinical response to cyclosporine, tacrolimus, and sirolimus, which support the role of T lymphocytes.

Question 26

What are clinical features of autoimmune lymphoproliferative syndrome (ALPS)?

Answer 26

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmunity (typically autoimmune cytopenias) and lymphoproliferation (lymphadenopathy and splenomegaly). There is also an increased risk of lymphoma. This disorder is caused by a defect in lymphocyte apoptosis.

Clinical Features:
Lymphoadenopathy and/or splenomegaly
Elevated α/β double-negative T cells
Defective lymphocyte apoptosis
Elevated IL-10, vitamin B12, or IL-18 levels
Autoimmune cytopenias with hypergammaglobulinemia
Positive family history

Question 27

What are the genetics of ALPS?

Answer 27

Type I—FAS mutation (can be somatic or germline)
Type Ib—FAS ligand mutation
Type IIa—Caspase-10 mutation

Question 28

How is ALPS treated?

Answer 28

Treatment—Cytopenias and lymphoproliferation are treated with immunosuppressives, such as corticosteroids, mycophenolate mofetil, cyclosporine, tacrolimus, or sirolimus. Bone marrow transplantation is curative.

Question 29

What are the genes involved in Addison’s disease?

Answer 29

HLA B8 and DR3

Question 30

What is the antibody against in Addison’s?

Answer 30

Autoantibody is to the adrenal cortex enzyme 21-hydroxylase, and it is found in 90% of recent-onset patients.

Question 31

What are the hormone levels in Addisons’s Disease?

Answer 31

Addison’s disease is a chronic disorder of adrenal cortex characterized by deficient production of glucocorticoids, mineralocorticoids, and androgens, with an increased secretion of adrenocorticotropic hormone (ACTH).

Question 32

What are the hormone levels in primary adrenal failure?

Answer 32

Decreased aldosterone with increased renin.

Question 33

What is the autoantibody in primary adrenal fialure?

Answer 33

Autoantibody to CYP21A2 (enzyme is necessary to make cortisol), involving both cellular and humoral injury.

Question 34

What is the genetic association of primary adrenal failure?

Answer 34

—HLA DRB*0404, DQ8, and MICA.5.1.

Question 35

What are the autoantibodies in DM type 1A?

Answer 35

Associated with autoantibodies to glutamic acid dehydrogenase (anti-GAD65), insulin, tyrosine phosphatase, and zinc T8 transporter. Destruction of beta cells probably requires T lymphocytes.

Question 36

What are the genetics of DM type 1A?

Answer 36

Family history of autoimmune diseases, monozygotic twins 30%. Ninety percent of patients will have the following haplotypes: DR3,DQ2 (DQ2 = DQA10501 and DQB10201) and DR4, DQ8 (DQA10301 and DQB10302).

Question 37

What are the autoantibodies in Type 1B DM?

Answer 37

Anti-insulin receptor antibodies block the ability of insulin to bind to its receptor. Thus, insulin levels are high.

Question 38

What conditions is type 1B DM associated with?

Answer 38

SLE and scleroderma

Question 39

What is insulin autoimmune syndrome? What is it associated with?

Answer 39

Insulin Autoimmune Syndrome—Autoantibody that reacts with insulin, which can be monoclonal or polyclonal. The monoclonal antibody is associated with Blymphocyte tumors. Polyclonal antibody follows therapy with sulfhydrylcontaining medications such as methimazole (i.e., treatment for Graves’ disease). Patients present with recurrent hypoglycemia.

Question 40

What does the biopsy of minimal change nephrotic syndrome show?

Answer 40

Effacement of visceral foot processes identified by electron microscopy (EM).

Question 41

What does the biopsy of membranous nephropathy show?

Answer 41

Diffuse thickening of glomerular basement membrane (GBM) with immunofluorescence revealing prominent granular staining of IgG and C3 along GBM. EM studies show epithelial foot process effacement with electrondense (i.e., immune complex deposits) distributed over the GBM.

Question 42

What is the biopsy of focal segmental glomerulosclerosis?

Answer 42

Segmental glomerular collapse with some focal glomeruli involved.

Question 43

What are teh nephritogenic antigens responsible for post-strep glomerulonephritis?

Answer 43

Nephritogenic antigens responsible for PSGN:
Nephritis-associated plasmin receptor (NAPir)
o Glycolytic enzyme with GADPH activity
Streptococcal pyogenic exotoxin B (SPEB)
o Cationic cysteine proteinase

Question 44

How is diagnosis of post-strep GN made?

Answer 44

Diagnosis—Low C3 with evidence of circulating immune complexes as well as cryoglobulins, rheumatoid factor, and elevated IgG. Based on combination of antecedent streptococcal infection or positive antistreptolysin O or antiDNAse B titers. Biopsy is only recommended when diagnosis is in question.

Question 45

What does the biopsy show for IgA nephropathy?

Answer 45

—Mesangial IgA staining on immunofluorescence. Elevated circulating polymeric IgA and complexes with IgA in the serum.

Question 46

What key immunologic process causes MPGN?

Answer 46

IgM immune complexes deposit on glomerular proteins and activate complement or via direct monoclonal IgM binding to glomerular proteins.

Question 47

What does the biopsy show in antiglomerular basement membrane (anti-GBM) disease?

Answer 47

Crescents over more than 50% of glomeruli and immunofluorescence of diseased glomeruli reveals staining of IgG along GBM (linear distribution).

Question 48

What is the autoantibody in anti-GBM?

Answer 48

circulating antibodies directed against α3 chain of type IV collagen. One third of patients have positive perinuclear antineutrophil cytoplasmic antibodies (pANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (cANCA). Patients with these circulating Abs have milder disease.

Question 49

What diseases is pauci-immune crescentic GN associated with? medications?

Answer 49

—Primary pauci-immune crescentic GN is secondary to vasculitis, including Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Related to activated T lymphocytes and autoantibodies. Pauci-immune crescentic GN is associated with the use of: -Propylthiouracil

• Hydralazine
• Penicillamine
• Minocycline

Question 50

What is the most common cause of immune complex mediated RPGN and what is it characterized by?

Answer 50

Hemolytic-uremic syndrome (HUS) is the primary cause, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.

Question 51

A 10-year-old girl presents to the emergency department with petechial rash on her extremities, bloody diarrhea, and decreasing urine output after consuming undercooked hamburger. Preliminary lab findings reveal Hgb 7, platelets 40,000, and schistocytes on peripheral smear. What is the most likely diagnosis?

Answer 51

Hemolytic-uremic syndrome