records of the Massachusetts General Hospital. Case 31-2005. A 60-year-old man with skin lesions and renal insufficiency" (2005). Rheumatology Publications and Presentations. Paper 142.

The molecular chaperone receptor-associated protein (RAP) is required for biosynthesis of megalin, an endocytic receptor for follicular thyroglobulin (Tg), the thyroid hormone precursor. RAP also binds to Tg itself, suggesting that it may affect Tg trafficking in various manners. To elucidate RAP function, we have studied the thyroid phenotype in RAP-knockout (RAP-KO) mice and found a reduction of Tg aggregates into thyroid follicles. Serum Tg levels were significantly increased compared with those of wild-type (WT) mice, suggesting a directional alteration of Tg secretion. In spite of these abnormalities, hormone secretion was maintained as indicated by normal serum thyroxine levels. Because Tg in thyroid extracts from RAP-KO mice contained thyroxine residues as in WT mice, we concluded that in RAP-KO mice, follicular Tg, although reduced, was nevertheless sufficient to provide normal hormone secretion. Serum TSH was increased in RAP-KO mice, and although no thyroid enlargement was observed, some histological features resembling early goiter were present. Megalin was decreased in RAP-KO mice, but this did not affect thyroid function, probably because of the concomitant reduction of follicular Tg. In conclusion, RAP is required for the establishment of Tg reservoirs, but its absence does not affect hormone secretion.

Megalin mediates transcytosis of thyroglobulin (Tg), the thyroid hormone precursor, resulting in its passage into the bloodstream. The process involves especially hormone-poor Tg, which may favour hormone secretion by preventing competition with hormone-rich Tg for proteolytic degradation. To gain more insight into the role of megalin, here we studied thyroid function and histology in megalin deficient mice compared with WT mice. As expected from the knowledge that megalin mediates Tg transcytosis, serum Tg levels were significantly reduced in homozygous (megalin−/−) mice, which, more importantly, were found to be hypothyroid, as demonstrated by significantly reduced serum free thyroxine and significantly increased serum thyroid stimulating hormone (TSH) levels. In heterozygous (megalin+/−) mice, in which megalin expression was normal, thyroid function was unaffected. Although the serological phenotype in megalin−/− mice was not associated with histological alterations or goiter, our results support a major role of megalin in thyroid hormone secretion.

A 60-year-old man was evaluated at the hospital because of renal failure. He had been well until a trip to Colorado three months earlier; one week after returning he reported fatigue, edema, and a rash on his arms and legs. Laboratory evaluation revealed anemia, renal insufficiency, microscopic hematuria, and proteinuria. Serum complement levels were decreased. A skin biopsy showed leukocytoclastic vasculitis. Testing for cryoglobulins and antineutrophil cytoplasmic antibodies was negative. A diagnostic procedure was performed.

A 12-year-old boy was admitted to the hospital with a two-day history of a rash and of swelling of the face, hands, and feet. On admission, he was afebrile and hypertensive, with pitting edema of the legs. Laboratory studies disclosed hematuria, proteinuria, urinary casts, and elevated blood urea nitrogen and creatinine levels. The discussant reviews the differential diagnosis of acute renal failure in children.

Secretion of thyroglobulin (Tg) by thyrocytes requires several endoplasmic reticulum (ER)-resident molecular chaperones. The receptor-associated protein (RAP), a known molecular chaperone, binds to Tg in thyroid cells shortly after biosynthesis. Here we investigated whether RAP is involved in Tg secretion by FRTL-5 cells. For this purpose, we studied Tg secretion by FRTL-5 cells transfected with a soluble RAP chimera, as a mean for interfering with endogenous RAP. We used a RAP-human IgG Fc (RAP-Ig) chimeric cDNA, which was designed in order to exclude the ER retention sequence of RAP and to allow generation of a secreted form of RAP. FRTL-5 cells were transiently transfected with the RAP-Ig cDNA or, as control, with a CD8-Ig cDNA. Media were collected at 24, 48 and 72 h after transfection. Secretion of fusion proteins and of Tg in the media was measured by ELISA. As expected, under standard culture conditions, RAP was not secreted into the media by FRTL-5 cells, even though it could be detected by Western blotting in cell extracts. In transfection experiments, fusion proteins were present in the media of FRTL-5 cells transfected with either RAP-Ig or CD8-Ig, indicating that transfection was successful. Although Tg was found in the media of FRTL-5 cells transfected with either CD8-Ig or RAP-Ig, a lower amount was found in cells transfected with RAP-Ig. Therefore, we concluded that RAP is involved in Tg secretion by FRTL-5 cells suggesting that RAP may function as a Tg molecular chaperone.

The present study was undertaken in order to investigate the nature of the glomerular damage in a form of experimental immune complex nephritis. The model of autologous immune complex nephritis (AIC) 1 (Heymann's nephritis) (1) was chosen for several reasons. First, the model bears a remarkable resemblance, in terms of ultrastructural and immunofluorescence features, to an important renal disease in man, membranous glomerulonephritis. Furthermore, the model is highly reproducible. In addition, the basic pathogenetic mechanism has been thoroughly documented (2-4). Briefly, the disease is produced in rats by immunization with homologous kidney preparations, which results in the formation of autoantibodies against a renal antigen, normally found in the brush border of proximal tubules. This antigen is presumed to enter the circulation in small amounts and combine with autoantibody to form complexes which deposit in glomeruli. 2 The complexes are detected as granular deposits of immunoglobulin and complement along the epithelial side of the glomerular basement membrane. The disease, like its human counterpart, is manifested by proteinuria, which is often heavy.

From the Division of Rheumatology, Department of Medicine, Brigham and Women’s Hospital (J.S.C.), and the Department of Pathology, Massachusetts General Hospital (R.T.M.) — both in Boston. A 36-year-old, right-handed man was admitted to the hospital because of seizures and severe hypertension. The patient had an 18-year history of intravenous drug abuse, including abuse of heroin and cocaine with needle sharing. One year before admission, he discontinued his use of illicit drugs and began to feel vaguely unwell. Three months before admission, tingling developed in the left toes and progressed to numbness in the foot; these symptoms were accompanied by recurrent vomiting, night sweats, intermittent diarrhea, abdominal pain, subjective fever, and a weight loss of 16 kg. He noted erythematous lumps over the shins and ankles; the lumps waxed and waned for a month before healing. Five weeks before admission, he was admitted to another hospital, where hypertension was diagnosed. The results of tests for hepatitis B virus and hepatitis C virus were reported to be positive. Supportive care included parenteral nutrition. After three weeks, he was discharged. One week later, shaking occurred in the patient’s left leg and spread to his left arm; he lost consciousness and had a witnessed generalized tonic–clonic seizure. He was taken to a second hospital, where another seizure was controlled with phenytoin sodium and a benzodiazepine. The initial blood pressure was 240/130 mm Hg. The urine was normal. Laboratory tests were performed (Tables 1 and 2). An electrocardiogram revealed sinus tachycardia with diffuse, nonspecific ST- and T-wave abnormalities. A lumbar puncture yielded acellular cerebrospinal fluid that was sterile on culture; the glucose level was 59 mg per milliliter (3.3 mmol per liter), and the protein level was 71 mg per deciliter. A computed tomographic (CT) scan of the brain was reported to show no evidence of intracranial hemorrhage. A cranial magnetic resonance imaging (MRI) study was believed to suggest the presence of a low-grade occipital neoplasm. Labetalol, clonidine, fluid, and electrolytes were given, and the hypertension diminished. On the fifth hospital day, the patient was discharged while taking phenytoin, labetalol, clonidine, trazodone, bupropion, omeprazole, and potassium chloride, and a follow-up visit at this hospital was scheduled. He promptly began to have numbness and “shooting pains” in the left foot and ankle, with dysesthesias in the foot; he also had local motor weakness, without low back pain or sciatic pain. Three days after presentation of case

Presentation of CaseA 36-year-old, right-handed man was admitted to the hospital because of seizures and severe hypertension.The patient had an 18-year history of intravenous drug abuse, including abuse of heroin and cocaine with needle sharing. One year before admission, he discontinued his use of illicit drugs and began to feel vaguely unwell. Three months before admission, tingling developed in the left toes and progressed to numbness in the foot; these symptoms were accompanied by recurrent vomiting, night sweats, intermittent diarrhea, abdominal pain, subjective fever, and a weight loss of 16 kg. He noted erythematous lumps over the shins . . .

BACKGROUND The value of measuring serial antineutrophil cytoplasmic autoantibody (ANCA) titers in guiding therapy among patients with ANCA-associated vasculitis is controversial. METHODS We measured serial titers of proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA by antigen-specific enzyme-linked immunosorbent assays (ELISAs) in 48 patients with ANCA-associated vasculitis who were followed up during remission at the Massachusetts General Hospital from 1990 through 2000 (mean follow-up, 46.2 months). We retrospectively assessed disease activity by Birmingham Vasculitis Activity Score (BVAS). RESULTS We found 21 episodes of fourfold or greater ANCA titer rises in 17 patients who were in complete remission (BVAS=0). Among eight patients who had 10 such titer rises and were not given increased immunosuppression, (group I), all suffered relapses after each episode (mean interval, 5.8 months), whereas among 11 patients, each with one titer rise, who received preemptive increased immunosuppression, (group II), only two relapses occurred, at 3 and 6 months. The difference in the cumulative incidence of relapses in a 1-year period between the two groups was 82% (P=0.0002). Changes in ANCA titers were also used to help guide therapy in the other 31 patients in the study; patients with slight titer rises often received incremental increases in immunosuppression, whereas those with falling titers received incremental decreases. The overall outcome in the entire group was favorable; 46 patients were alive at the end of the study; two died of unrelated diseases. CONCLUSION Serial measurements of PR3- and MPO-ANCA titers in patients with ANCA-associated vasculitis during remission can help predict relapses, and preemptive increases in immunosuppression following fourfold titer rises reduces the risk of relapses. Moreover, adjustment of immunosuppression based on lesser titer changes appears to result in a favorable outcome.

Hormone secretion by thyrocytes occurs by fluid phase uptake and lysosomal degradation of the prohormone thyroglobulin (Tg). However, some Tg internalized by megalin bypasses lysosomes and is transcytosed across cells and released into the bloodstream. Because the hormone content of Tg is variable, we investigated whether this affects transcytosis. We found that rat Tg with a low hormone content [low-hormonogenic rat Tg (low-horm-rTg)] is transcytosed by megalin across thyroid FRTL-5 cells to a greater extent than rat Tg with a high hormone content [hormonogenic rat Tg (horm-rTg)]. In immunoprecipitation experiments, the Tg sequence Arg-2489-Lys-2503 (required for binding to megalin and heparan sulfate proteoglycans) was found to be more exposed in low-horm-rTg, which accounted for its preferential transcytosis. Thus, removal of surface heparan sulfate proteoglycans from FRTL-5 cells or blocking of 2489-2503 reduced transcytosis of low-horm-rTg to a greater extent than that of horm-rTg. Preferential transcytosis of low-horm-rTg affected hormone release. Thus, the increase in hormone release from horm-rTg in FRTL-5 cells determined by megalin blocking (due to reduced transcytosis and enhanced Tg degradation) was rescued by low-horm-rTg, suggesting that megalin is required for effective hormone release. This finding was confirmed in a small number of megalin-deficient mice, which had serological features resembling mild hypothyroidism. Reduced hormone formation within Tg in vivo, due to treatment of rats with aminotriazole or of patients with Graves' disease with methimazole, resulted in increased Tg transcytosis via megalin, in confirmation of results with FRTL-5 cells. Our study points to a major role of megalin in thyroid homeostasis with possible implications in thyroid diseases.

Correspondence Re: GAL AA, VELASQUEZ A. ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY IN THE ABSENCE OF WEGENER’S GRANULOMATOSIS OR MICROSCOPIC POLYANGIITIS: IMPLICATIONS FOR THE SURGICAL PATHOLOGIST. MOD PATHOL 2002;15:197–204.