26

CASE 26


Brad, a 25-year-old man, was referred to your endocrinology service by his family physician with apparently multiple autoimmune-type manifestations. He first came to his family physician’s attention several years earlier with weight gain, listlessness, general fatigue, and coarsening of the skin. After multiple attempts to establish a diagnosis his physician finally arrived at the conclusion (seemingly confirmed by thyroid function tests) that he was hypothyroid. There was no antecedent viral illness that anyone could remember, and no other family members were affected. These problems seemed to resolve with conventional thyroid replacement therapy with levothyroxine. About 2 years later fatigue recurred despite evidence for normal thyroid replacement. Blood work at this time was suggestive of adrenocortical involvement, and indeed a diagnosis of Addison’s disease was pursued. Measurement of serum and urinary adrenocortical hormones supported this hypothesis too, and again he was treated effectively with replacement mineralcorticoid, fludrocortisone (Fluorcortef/Florinef). Once again there was no evidence of any precipitating event to this disorder (drugs/infection) and no family members were affected. Finally, just 3 weeks ago he presented with an oral Candida albicans infection, which has been inordinately resistant to topical antifungal agents, and his physician is at a total loss. He is essentially unsure whether Brad is just “unlucky” or whether all of these events are tied together and are independent manifestations of some disorder he has not heard of. The answer is in fact likely to be the latter.



QUESTIONS FOR GROUP DISCUSSION



1. Autoimmune polyendocrinopathy syndrome (APS-1) has been mapped to a unique gene, AIRE (AutoImmune REgulator), on chromosome 21. What is the role of the protein that it encodes?

2. What is the criteria for a diagnosis of APS-I? Of APS-II? What technique is used to confirm a mutation in the AIRE gene?

3. Review the role of the thymus in tolerance induction (see Case 2 and the discussion on positive and negative selection).

4. Explain the significance of the fact that an equivalent gene in the mouse has been shown to be expressed in the thymus at sites where negative selection occurs (see Case 2).

5. What is the significance of the fact that a number of organ-specific antigens are actually now known to be expressed in the thymus (e.g., insulin, myelin/oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), and glutamic acid decarboxylase)?

6. Knockout mice for the AIRE gene equivalent do not express the AIRE equivalent protein. Explain the significance of the fact that they have multiple organ-specific immune syndromes (e.g., orchitis, retinitis), and have antibody titers to multiple organ-specific antibodies.

7. The knockout mice (question 4) have no obvious immune cell abnormalities when compared with wild-type mice. However, there is a subtle increase in thymic epithelial cells in the medulla, as determined using CD80 (B7-1) and CR-1 (antibody specific to thymic epithelial cells). What is the role of CD80 in T cell activation?

8. The knockout mice (question 4) also had an increased number of activated cells in the periphery as determined using CD44 (high) and CD62L (low). CD44 is a glycoprotein that binds to hyaluronan. CD62L is also known as l-selectin, an adhesive molecule that binds to carbohydrates on the endothelium to induce cell rolling. What is the significance of an increase in activated T cells in the periphery in these knockout mice?

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Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on 26

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