Six patients with Hashimoto thyroiditis (HT) and associated encephalopathy (HE) are described and compared with 14 well-documented cases retrieved from the literature. HE typically affects patients when they are euthyroid and, in an appropriate clinical situation, antithyroid autoantibodies are the main indicators of HE. Since clinical features of HE are unspecific, other aetiologies such as infectious, metabolic, toxic, vascular, neoplastic, and paraneoplastic causes have to be excluded. Our own six cases and those from the literature show that two types of initial clinical presentation can be differentiated: a vasculitic type with stroke-like episodes and mild cognitive impairment in nine patients, and a diffuse progressive type with dementia, seizures, psychotic episodes or altered consciousness in 11 patients. These types may overlap, particularly in the long-term course without treatment. Response to steroids was usually excellent with complete remission in 80%. Eighteen of the 20 patients were women. Characteristic, though unspecific, findings were abnormal EEG (90%) and CSF (80%). Together with quantitative neuropsychological testing, these proved sensitive for monitoring the efficacy of therapy. Conversely, antithyroid autoantibody titres did not correlate with the severity or type of clinical presentation. The link between HE and HT is not clear. A pathogenetic role for antithyroid autoantibodies in the central nervous system seems unlikely.

BACKGROUND

Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) polymorphisms have been widely examined for their associations with autoimmune thyroid diseases [Graves' disease (GD) and Hashimoto thyroiditis (HT)], but their relative population effect remains unclear.

OBJECTIVE

The aim was to generate large-scale evidence on whether the CTLA-4 polymorphisms (A49G and CT60) and haplotypes thereof increase the susceptibility to GD and/or HT.

METHODS

Meta-analyses of group-level data were reviewed from 32 (11,019 subjects) and 12 (4,479) published and unpublished studies for the association of the A49G polymorphism with GD and HT, respectively (PubMed and HuGeNet search until July 2006). There were 15 (n = 7246) and six (n = 3086) studies available for the CT60 polymorphism, respectively. Meta-analyses of individual-level data from 10 (4906 subjects) and five (2386) collaborating teams for GD and HT, respectively, were also reviewed.

METHODS

Association of gene variants and haplotypes with GD and HT was measured.

RESULTS

Group-level data suggested significant associations with GD and HT for both A49G [odds ratios 1.49 (P = 6 x 10(-14)) and 1.29 (P = 0.001) per G allele, respectively] and CT60 [1.45 (P = 2 x 10(-9)) and 1.64 (P = 0.003) per G allele, respectively]. Results were consistent between Asian and Caucasian descent subjects. Individual-level data showed that compared with the AA haplotype, the risk conferred by the GG haplotype was 1.49 (95% confidence interval 1.31,1.70) and 1.36 (95% confidence interval 1.16,1.59) for GD and HT, respectively. Data were consistent with a dose-response effect for the G allele of CT60.

CONCLUSIONS

The CT60 polymorphism of CTLA-4 maps an important genetic determinant for the risk of both GD and HT across diverse populations.

Overexpression of alpha-synuclein and oxidative stress has been implicated in the neuronal cell death in Parkinson's disease. Alpha-synuclein associates with mitochondria and excessive accumulation of alpha-synuclein causes impairment of mitochondrial functions. However, the mechanism of mitochondrial impairment caused by alpha-synuclein is not fully understood. We recently reported that alpha-synuclein associates with mitochondria and that overexpression of alpha-synuclein causes nitration of mitochondrial proteins and release of cytochrome c from the mitochondria [Parihar M.S., Parihar A., Fujita M., Hashimoto M., Ghafourifar P. Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci. 2008a;65:1272-1284]. The present study shows that overexpression of alpha-synuclein A53T or A30P mutants or wild-type in human neuroblastoma cells augmented aggregation of alpha-synuclein. Immunoblotting and immuno-gold electron transmission microscopy show localization of alpha-synuclein aggregates within the mitochondria of overexpressing cells. Overexpressing cells show increased mitochondrial reactive oxygen species, increased protein tyrosine nitration, decreased mitochondrial transmembrane potential, and hampered cellular respiration. These findings suggest an important role for mitochondria in cellular responses to alpha-synuclein.

Certain autoimmune sera contain antibodies against a nucleolar ribonucleoprotein particle associated with 7-2-RNA (R. Reddy et al. (1983) J. Biol. Chem. 258, 1383; C. Hashimoto and J. A. Steitz (1983) J. Biol. Chem. 258, 1379). In this study, we showed by immunofluorescence microscopy that antibodies reactive with 7-2-ribonucleoprotein immunolocalized in the granular regions of actinomycin D and 5,6-dichloro-1-beta-D-ribofurano-sylbenzimidazole (DRB)--segregated nucleoli from Vero cells. By electron microscopic immunocytochemistry, antigen-antibody complexes were located in the granular component of transcriptionally active nucleoli from rat liver hepatocytes and HeLa cells. Anti-7-2-RNP antibodies from two autoimmune sera immunoprecipitated a major protein of Mr 40,000 from [35S] methionine--labeled HeLa cell extract. The immunolocalization data suggest that 7-2-ribonucleoprotein may be involved in stages of ribosome biogenesis which take place in the granular component of the nucleolus, i.e., assembly, maturation, and/or transport of preribosomes.

BACKGROUND

Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from families with several members with the disease and in their first-degree relatives.

METHODS

A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case-control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (CTLA4) and protein tyrosine phosphatase (PTPN22) variants with susceptibility to multiple sclerosis.

RESULTS

46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0.009) but not in families without a history of other autoimmune disorders (p=0.90).

CONCLUSIONS

The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.

It is now well established that autophosphorylation of a threonine residue located next to each calmodulin-binding domain in the subunits of type II Ca2+/calmodulin-dependent protein kinase causes the kinase to remain active, although at a reduced rate, after Ca2+ is removed from the reaction. This autophosphorylated form of the kinase is still sensitive to Ca2+/calmodulin, which is required for a maximum catalytic rate. After removal of Ca2+, new sites are autophosphorylated by the partially active kinase. Autophosphorylation of these sites abolishes sensitivity of the kinase to Ca2+/calmodulin (Hashimoto, Y., Schworer, C. M., Colbran, R. J., and Soderling, T. R. (1987) J. Biol. Chem. 262, 8051-8055). We have identified two pairs of homologous residues, Thr305 and Ser314 in the alpha subunit and Thr306 and Ser315 in the beta subunit, that are autophosphorylated only after removal of Ca2+ from an autophosphorylation reaction. The sites were identified by direct sequencing of labeled tryptic phosphopeptides isolated by reverse-phase high pressure liquid chromatography. Thr305-306 is rapidly dephosphorylated by purified protein phosphatases 1 and 2A, whereas Ser314-315 is resistant to dephosphorylation. We have shown by selective dephosphorylation that the presence of phosphate on Thr305-306 blocks sensitivity of the kinase to Ca2+/calmodulin. In contrast, the presence of phosphate on Ser314-315 is associated with an increase in the Kact for Ca2+/calmodulin of only about 2-fold, producing a relatively small decrease in sensitivity to Ca2+/calmodulin.

Polyglandular autoimmune syndromes (PAS) are rare polyendocrinopathies characterized by the failure of several endocrine glands as well as nonendocrine organs, caused by an immune-mediated destruction of endocrine tissues. This article summarizes extensive clinical, epidemiological, serological, and genetic data of a large collective of patients with PAS (n = 360). Since 1988, more than 15,000 adult patients with endocrine diseases have been screened at the endocrine center of the Mainz University, and 151 of 360 patients with PAS have regularly been followed. Type 1 diabetes, Graves' disease, Hashimoto thyroiditis, Addison's disease, vitiligo, alopecia, hypogonadism, and pernicious anemia were observed in 61%, 33%, 33%, 19%, 20%, 6%, 5%, and 5%, respectively. The most common disease combination was type 1 diabetes and autoimmune thyroid disease. In most patients, type 1 diabetes was the first manifestation of PAS (48%). The longest time intervals between manifestations of the first and second immune endocrinopathies occurred between type 1 diabetes and thyroid disease (13.3 +/- 11.8 yr) and between vitiligo and thyroid disease (16.3 +/- 13.3 yr), but a shorter time interval was observed between Addison's and thyroid diseases. Of the 471 patients with type 1 diabetes screened, 83 (17.6%) were positive for PAS. Subsequently, sera of 126 patients with PAS, 287 with type 1 diabetes, and 303 matched controls were compared for human leukocyte antigens. Patients with PAS had significantly higher frequencies of the human leukocyte antigens A24, A31, B8, B51, B62, DR3, and DR4 (relative risk, 2.35, 2.74, 2.47, 7.17, 2.22, 1.94, and 2.46) vs. controls, and for A31, B15, B52, B55, DR2, DR11, and DR13 (relative risk, 2.51, 7.96, 3.99, 5.36, 4.46, 2.89, and 3.26) vs. type 1 diabetes patients without PAS. In conclusion, patients with autoimmune endocrine disease should be followed on a regular basis. In subjects at risk for PAS, functional screening every 3 yr is warranted. If clinical disease is present, serological measurement of organ-specific antibodies should follow.

OBJECTIVE

Analyses of families with multiple autoimmune disorders have revealed a functional polymorphism, 620W, in the intracellular tyrosine phosphatase gene PTPN22 as a predisposing factor for type 1 diabetes, seropositive rheumatoid arthritis, systemic lupus erythematosus, and Hashimoto thyroiditis, and the presence of the PTPN22 protein appears to herald the development of autoantibodies in these disorders. This study therefore examined whether the functionally relevant PTPN22 polymorphism is associated with Wegener's granulomatosis (WG).

METHODS

A population-based study was performed for the PTPN22 polymorphism in 199 patients with WG and in 399 healthy individuals. The R620W variation was investigated by simple restriction fragment-length polymorphism analysis.

RESULTS

The PTPN22 620W allele frequency was significantly increased in antineutrophil cytoplasmic antibody (ANCA)-positive WG patients compared with healthy controls (P < 0.001). The association was particularly striking in patients with kidney, lung, eye, and peripheral nervous system involvement (i.e., those with generalized WG).

CONCLUSIONS

The PTPN22 620W allele appears to be involved in the pathogenesis of WG, and ANCA positivity seems to be the hallmark.

cDNA clones for rat acyl-CoA oxidase were isolated. The 3.8-kilobase mRNA sequence of the enzyme was completely covered by two overlapping clones. The composite cDNA sequence consisted of 3741 bases and contained a 1983-base open reading frame which encodes a polypeptide of 661 amino acid residues. Two species of acyl-CoA oxidase cDNA were identified. They differed in their coding nucleotide sequences, only within a small region. They contained the same number of nucleotides and can be translated in a common reading frame. They are 55% and 50% homologous in the above region at the nucleotide and the amino acid levels, respectively. Both types of cDNA were isolated from a library constructed from mRNA of a single rat, thereby suggesting the occurrence of two species of acyl-CoA oxidase in each rat. The amino terminus of the enzyme was determined to be N-acetylmethionine, which corresponds to the initiator methionine, thus confirming the absence of a terminal presequence. We reported previously that a purified preparation of the enzyme contained three polypeptide components, A, B, and C, and suggested that components B and C are produced by a proteolytic cleavage of component A (Osumi, T., Hashimoto, T., and Ui, N. (1980) J. Biochem. (Tokyo) 87, 1735-1746). We located components B and C on the amino- and the carboxyl-terminal sides of component A. Possible functional significances of several stretches of amino acids of the enzyme are discussed, based on the sequence comparison data between rat and yeast acyl-CoA oxidases.

Hashimoto's encephalopathy is a term used to describe an encephalopathy of presumed autoimmune origin characterised by high titres of antithyroid peroxidase antibodies. In a similar fashion to autoimmune thyroid disease, Hashimoto's encephalopathy is more common in women than in men. It has been reported in paediatric, adult and elderly populations throughout the world. The clinical presentation may involve a relapsing and remitting course and include seizures, stroke-like episodes, cognitive decline, neuropsychiatric symptoms and myoclonus. Thyroid function is usually clinically and biochemically normal.Hashimoto's encephalopathy appears to be a rare disorder, but, as it is responsive to treatment with corticosteroids, it must be considered in cases of 'investigation negative encephalopathies'. Diagnosis is made in the first instance by excluding other toxic, metabolic and infectious causes of encephalopathy with neuroimaging and CSF examination. Neuroimaging findings are often not helpful in clarifying the diagnosis. Common differential diagnoses when these conditions are excluded are Creutzfeldt-Jakob disease, rapidly progressive dementias, and paraneoplastic and nonparaneoplastic limbic encephalitis. In the context of the typical clinical picture, high titres of antithyroid antibodies, in particular antithyroid peroxidase antibodies, are diagnostic. These antibodies, however, can be detected in elevated titres in the healthy general population. Treatment with corticosteroids is almost always successful, although relapse may occur if this treatment is ceased abruptly. Other forms of immunomodulation, such as intravenous immune-globulin and plasma exchange, may also be effective. Despite the link to autoimmune thyroid disease, the aetiology of Hashimoto's encephalopathy is unknown. It is likely that antithyroid antibodies are not pathogenic, but titres can be a marker of treatment response. Pathological findings can suggest an inflammatory process, but features of a severe vasculitis are often absent. The links between the clinical pictures, thyroid disease, auto-antibody pattern and brain pathology await further clarification through research. It may be that Hashimoto's encephalopathy will be subsumed into a group of nonvasculitic autoimmune inflammatory meningoencephalopathies. This group may include disorders such as limbic encephalitis associated with voltage-gated potassium channel antibodies. Some authors have suggested abandoning any link to Hashimoto and renaming the condition 'steroid responsive encephalopathy associated with autoimmune thyroiditis' to better reflect current, if limited, understanding of this condition.

We retrospectively analyzed 26 patients with thyroid lymphoma (TL). Patients were mostly females, with a median age of 59 yr, presenting a rapidly growing nodular goiter with or without cervical adenopathy, without symptoms related to lymphoma for 81% and hypothyroidism in 61%. A previous history of Hashimoto thyroiditis was observed in 11 patients. Six different subtypes of lymphoma were observed: 13 of 26 (50%) had diffuse large B cell lymphoma, 6 (23%) mucosa- associated lymphoid tissue (MALT) lymphoma, 3 (12%) had follicular lymphoma, 2 (7%) had Hodgkin's disease, 1 (4%) had small lymphocytic lymphoma, and 1 (4%) had Burkitt's lymphoma. Diffuse large B cell lymphoma patients presented a compressive multinodular goiter, cervical adenopathy (66%), disseminated disease (50%), and poor performance status, with a poor prognosis (5-yr survival at 44%) despite a treatment based on a multidrug regimen. MALT lymphoma arose in patients with previous history of Hashimoto disease, was localized in all but 1, and was biologically associated with hypothyroidism and a high level of serum antithyroid antibodies. With total thyroidectomy, prognosis was good (5-yr survival at 100%). We did not find any routine clinical or biological parameters that could predict the evolution from Hashimoto's thyroiditis to MALT lymphoma. In conclusion, we confirmed the histological heterogeneity of TL corresponding to different clinical presentations and different prognoses.

BACKGROUND

The development of antibodies to thyroid peroxidase, thyroglobulin, and thyroid-stimulating hormone (TSH) receptor is a main feature of autoimmune thyroid diseases.

OBJECTIVE

To investigate whether complete removal of thyroid antigens results in the abatement of humoral thyroid autoimmunity.

METHODS

Retrospective chart review study of patients treated and monitored with a standard prospective protocol.

METHODS

University hospital in Pisa, Italy, between 1976 and 1994.

METHODS

182 patients with differentiated thyroid carcinoma and serum antibodies to thyroid peroxidase, thyroglobulin, or TSH receptor due to coexistent clinical Hashimoto thyroiditis, Graves disease, or focal autoimmune thyroiditis.

METHODS

Total thyroidectomy and radioiodine treatment to ablate residual or metastatic thyroid tissue. Regular follow-up with iodine-131 whole-body scanning and serum thyroglobulin measurement. Mean follow-up (+/-SD) was 10.1 +/- 4.1 years (range, 4 to 20 years).

METHODS

Serum antibodies to thyroid peroxidase, thyroglobulin, and TSH receptor.

RESULTS

Thyroid peroxidase, thyroglobulin, and TSH-receptor antibodies progressively disappeared after the initial treatment. The median disappearance time was 6.3 years for thyroid peroxidase antibodies and 3.0 years for thyroglobulin antibodies. There was a statistically significant correlation between the disappearance of thyroid tissue and that of thyroid antibodies. The coexistence of Hashimoto thyroiditis or Graves disease with thyroid cancer did not modify the pattern of disappearance of thyroid antibody compared with patients with focal autoimmune thyroiditis.

CONCLUSIONS

Complete ablation of thyroid tissue with its antigenic components results in the disappearance of antibodies to all major thyroid antigens, thus supporting the concept that continued antibody production depends on the persistence of autoantigen in the body.

According to the literature thyroid nodules are quite rare in the first two decades of life. However, there are some exceptions, relating to areas with an iodine deficiency or affected by radioactive fallout, where the risk of nodules and carcinomas is increased. Therefore, it is a great challenge for the physician to distinguish between benign and malignant lesions preoperatively, and not only in these areas of greater risk. A careful work-up, comprising the patient's history, clinical examination, laboratory tests, thyroid ultrasound, scintigraphy, fine-needle aspiration biopsy (FNAB) and molecular studies, is mandatory to improve the preoperative diagnosis. The differential diagnosis should also include benign thyroid conditions such as: (i) congenital hypothyroidism due to dyshormonogenesis or ectopy, (ii) thyroid hemiagenesis, (iii) thyroglossal duct cyst, (iv) simple goiter, (v) cystic lesion, (vi) nodular hyperplasia, (vii) follicular adenoma, (viii) Graves' disease and (ix) Hashimoto thyroiditis, all of which can predispose to the development of thyroid nodules. The majority of thyroid carcinomas derive from the follicular cell (papillary, follicular, insular and undifferentiated (or anaplastic) thyroid carcinoma), whereas medullary thyroid carcinoma derives from calcitonin-producing cells. Inherited forms of thyroid cancer may occur, especially in relation to medullary thyroid carcinoma. FNAB is a critical factor in establishing the preoperative diagnosis. However, we should keep in mind the fact that a conventional cytological evaluation can miss the neoplastic nature of a lesion and the employment of immunocytochemical and molecular studies of aspirates from FNAB can give us a more precise diagnosis of neoplasia in thyroid nodules once they are detected.

Two synthetic peptides containing the previously identified calmodulin (CaM)-binding domain of Ca2+/CaM-dependent protein kinase II (CaM-kinase II) (residues 296-309, Payne, M. E., Fong, Y.-L., Ono, T., Colbran, R. J., Kemp, B. E., Soderling, T. R., and Means, A. R. (1988) J. Biol. Chem. 263, 7190-7195) were phosphorylated by Ca2+/CaM-independent forms of the kinase. In the presence of EGTA, CaMK-(290-309) was phosphorylated exclusively on threonine residues (Km = 13 microM; Vmax = 211 nmol/min/mg). When the phosphorylated product was analyzed by reversed-phase high performance liquid chromatography (HPLC) two radioactive peaks were resolved. The first peak contained CaMK-(290-309) phosphorylated on Thr306, whereas the second peak contained CaMK-(290-309) phosphorylated on Thr305. However, under the same conditions CaMK-(294-319) was phosphorylated predominantly (approximately 70%) on serine residues (Km = 23 microM; Vmax = 99 nmol/min/mg) and HPLC analysis revealed a single major radioactive peak predominantly (more than 90%) phosphorylated at Ser314. Phosphorylation of both peptides was completely blocked in the presence of Ca2+ and a stoichiometric amount of CaM. Samples of each phosphorylated peptide were tested for CaM-binding ability by two procedures and compared to the nonphosphorylated peptides. Phosphorylation of either Thr305 or Thr306 greatly reduced the interaction between CaMK-(290-309) and CaM, whereas phosphorylation of Ser314 did not affect the ability of CaMK-(294-319) to bind CaM. These results indicate that Thr305 and/or Thr306 may be the Ca2+/CaM-independent autophosphorylation site(s) responsible for the loss of ability of CaM-kinase II to bind and be activated by Ca2+/CaM (Hashimoto, Y., Schworer, C. M., Colbran, R. J., and Soderling, T. R., J. Biol. Chem. 262, 8051-8055).

It has been claimed that the inositol 1,4,5-trisphosphate-sensitive calcium pool in liver and pancreatic acinar cells is located in specified organelles ("calciosomes") which are characterized by their content of the calcium-binding protein calsequestrin (Volpe, P., Krause, K. H., Hashimoto, S., Zorzato, F., Pozzan, T., Meldolesi, J., and Lew, D. P. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 1091-1095). We show here that the inositol 1,4,5-trisphosphate-sensitive compartment of rat liver does not contain calsequestrin-like material. Instead four non-membraneous calcium-binding glycoproteins with approximate molecular masses of 59, 60, 80, and 90 kDa were found. The 59-, 80-, and 90-kDa proteins were of the high mannose-rich type, the carbohydrate moiety of the 60-kDa protein was of the complex hybrid type with terminal galactoses. All four proteins had high affinity binding sites for calcium (KD between 1 and 5 microM) and from 1 to 5 binding sites/molecule. The 80- and the 90-kDa proteins had also low affinity binding sites (KD 400 and 600 microM, respectively, with 13 and 15 binding sites/molecule, respectively). A comparison of the NH2-terminal sequences revealed that the 60-kDa calcium-binding protein represents the rat liver calregulin, whereas the 90-kDa calcium-binding protein represents grp94. The sequences did not reveal any relationship of the 80-kDa protein with grp78, or of the 59-kDa protein with protein disulfide isomerase.

Several studies report a higher rate of papillary thyroid carcinomas (PTC) in patients with Hashimoto thyroiditis (HT), indicating a possible correlation between the two diseases. We studied a group of 89 subjects undergoing surgery for thyroid carcinomas compared with a control group of 89 subjects operated on for normofunctioning goiter, and a second group of 47 patients undergoing total thyroidectomy for HT. Association with HT was found in 19 of the 71 PTC subjects (26.7%) and in 8 goiter patients (8.9%), which was a significant difference (P < 0.02). Thirteen of the HT patients, mostly with the nodular form, showed coexistent PTC (27.6%). HT and PTC coexisted in several morphological, immunohistochemical, and biomolecular aspects; increased incidence of PTC in HT patients might therefore indicate that HT is a precursor of thyroid cancer. Further studies are required, however, in order to confirm this hypothesis; until then, HT patients should undergo careful clinical and technical follow-up.

BACKGROUND

The cumulative risk of non-Hodgkin lymphoma (NHL) in Sweden by age 80 years has increased to 1.1 in women and 1.6% in men in 2011. Increased risk of NHL associated with personal histories of some autoimmune diseases (ADs) is known. It is unclear whether there are other NHL-related ADs and whether this association holds across different sex, age and year of diagnosis, or NHL histological subtypes.

METHODS

Over an average of 9.4-year (maximum 47 years) follow-up of 878 161 patients diagnosed in 1964-2010 with 33 different ADs, 3096 subsequent NHL were diagnosed (data: Swedish Cancer Registry).

RESULTS

Of 33 studied ADs, 21 showed significantly increased risk of NHL; 6 of them tended to increase the risk and none significantly decreased it. The overall standardized incidence ratio (SIR) for NHL after ADs was 1.6 [novel findings: immune thrombocytopenic purpura (ITP) = 7.5, polymyositis/dermatomyositis = 4.1, primary biliary cirrhosis = 3.9, myasthenia gravis = 2.2, Behcet = 1.7, rheumatoid fever = 1.7, ulcerative colitis = 1.5, polymyalgia rheumatica = 1.4, and chronic rheumatic heart disease = 1.4; confirmatory findings: autoimmune hemolytic anemia = 27.2, Sjögren = 4.9, Celiac = 4.8, systemic lupus erythematosus = 4.4, polyarteritis nodosa = 2.9, discoid lupus erythematosus = 2.7, sarcoidosis = 2.6, Crohn = 2.1, systemic sclerosis = 2.1, rheumatoid arthritis = 2.0, and Hashimoto/hypothyroidism and psoriasis = 1.4]. SIR for NHL diagnosis before age 60 (2.2) was significantly higher than that in older ages (age ≥60: 1.5). The SIRs in women or men and in period 1993-2010 or 1964-1992 were similar. Risk of all common NHL histology subtypes significantly increased after ADs (cutaneous/peripheral T cell and anaplastic large T and null cell = 2.2; small B-cell lymphocytic = 1.7; diffuse large B cell = 1.6; follicular and mantel cell = 1.3).

CONCLUSIONS

Many of 33 studied ADs (except for ankylosing spondylitis, diabetes type I graves/hyperthyroidism, multiple sclerosis, chorea minor, and pernicious anemia), especially when diagnosed at younger ages, were associated with higher risk of NHL. However, the absolute risk of NHL in many ADs is still small.

Here we report on 12 affected members of a family with Bannayan-Riley-Ruvalcaba syndrome. We present clinical evidence of overlap between Bannayan-Zonana syndrome. Riley-Smith syndrome, and Ruvalcaba-Myhre syndrome in this autosomal dominantly inherited condition. We expand the phenotypic spectrum to include Hashimoto thyroiditis, which occurred in 7 of our cases. Finally, we discuss the relationship between the syndrome and juvenile polyposis of infancy.

OBJECTIVE

To determine if the prevalence of autoimmunity among relatives of patients with juvenile rheumatoid arthritis (JRA) is greater than that among relatives of healthy volunteer control subjects.

METHODS

Interviews were used to obtain histories of the following disorders among living first- and second-degree relatives of 110 patients and 45 controls: alopecia areata, ankylosing spondylitis, dermatomyositis, Graves' disease, Hashimoto thyroiditis, insulin-dependent diabetes mellitus, inflammatory bowel disease, iritis, JRA, multiple sclerosis, psoriasis, RA, systemic lupus erythematosus, and vitiligo. Chi-squares, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated. Families of 23 JRA affected sibpairs were interviewed subsequently.

RESULTS

There were no significant differences between patients and controls with regard to age, sex, ethnicity, or family size. Patients had 1,228 relatives and controls had 496 relatives. Of all the relatives of the patients, 155 had at least 1 autoimmune disorder, compared with 20 relatives of the controls (12.6% versus 4.0%; OR 3.4 [95% CI 2.1-5.7], P < 0.000001). The prevalence of autoimmunity was increased in first-degree and in second-degree relatives of patients (16.1% and 10.6%, respectively). The prevalence of Hashimoto thyroiditis was significantly higher in the relatives of patients (OR 3.5 [95% CI 1.6-7.9], P = 0.0008). The prevalences of other disorders were not significantly different. JRA affected sibpair families had an increased prevalence of autoimmunity (15.0%). A history of arthritis was found significantly more frequently in the JRA affected sibpair families, but not in the simplex families.

CONCLUSIONS

These data demonstrate that the prevalence of autoimmunity is significantly higher among first- and second-degree relatives of JRA patients. This suggests that clinically different autoimmune phenotypes may share common susceptibility genes, which may act as risk factors for autoimmunity.

Calcineurin (CaN) contains an autoinhibitory element (residues 457-482) 43 residues COOH-terminal of the calmodulin-binding domain (Hashimoto, Y., Perrino, B. A., and Soderling, T. R. (1990) J. Biol. Chem. 265, 1924-1927) that regulates the Ca(2+)-dependent activation of its phosphatase activity. Substitution of Arg476 and Arg477 or Asp467 to Ala in the autoinhibitory peptide 457-482 significantly decreased its inhibitory potency. CaN A subunits with these residues mutated to Ala were coexpressed with the Ca(2+)-binding B subunit using the baculovirus/Sf9 cell system. Kinetic analysis showed that although the purified mutants had no activity in the absence of calcium, they were less dependent than the wild-type enzyme on calcium and calmodulin for activity. To determine if additional autoinhibitory motifs were present in the COOH terminus of calcineurin, the A subunit was truncated at residues 457 or 420 and co-expressed with B subunit. The Vmax values of both truncation mutants with or without Ca2+ were increased relative to wild-type calcineurin. The increased Ca(2+)-independent activity of CaN420 relative to CaN457 indicates the presence of additional autoinhibitory element(s) within residues 420-457. CaN420 had similar high Vmax values with or without Ca2+, but the Km value for peptide substrate was increased 5-fold to 125 microM in the absence of Ca2+. The Km values of all the expressed calcineurin species were increased in the absence of Ca2+. The CaN A or CaN A420 subunits alone have low Vmax and high Km (115 microM) values even in the presence of Ca2+. These results indicate that 1) there are several autoinhibitory motifs between the CaM-binding domain and the COOH terminus that are relieved by Ca2+ binding to CaM and the B subunit, 2) Ca2+ binding to the B subunit also regulates enzyme activity by lowering the Km of the catalytic subunit for substrate, 3) binding of the B subunit is required for high Vmax values even after removal of the autoinhibitory domain. These results are consistent with synergistic activation of calcineurin by Ca2+ acting through both CaM and the B subunit.

Previous family and twin studies have indicated that Graves' disease has a heritable component. Family studies have also shown that some autoimmune disease cluster in families and genetic studies have been able to show shared susceptibility genes. In the present nation-wide study we describe familial risk for Graves' disease among parents and offspring, singleton siblings, twins and spouses with regard to age of onset, gender and number and type of affected family members. Additionally familial association of Graves' disease with any of 33 other autoimmune and related conditions was analyzed. The Swedish Multigeneration Register on 0-75-year-old subjects was linked to the Hospital Discharge Register from years 1987-2007. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalized for Graves' disease compared to those whose relatives were unaffected. The total number of hospitalized Graves' patients was 15,743. Offspring with an affected family member constituted 3.6% of all patients among offspring. The familial SIR was 5.04 for individuals whose sibling was affected but it increased to 310 when two or more siblings were affected; the SIR in twins was 16.45. Familial risks were higher for males than for females. The SIR was increased to 6.22 or 30.20 when parental age was limited to 50 or 20 years, respectively. Graves' disease associated with 19 other autoimmune and related conditions, including Addison's disease, type 1 diabetes mellitus, Hashimoto/hypothyroidism, pernicious anemia, polymyositis/dermatomyositis, myasthenia gravis, discoid lupus erythematosus and localized scleroderma. Remarkably, there was a high disease concordance of 2.75 between spouses. The clustering between spouses suggests environmental effects on Graves' disease which may contribute to the observed gender effects. The demonstrated high risks should be considered in clinical counseling and in prevention plans.

BACKGROUND

Autoimmune diseases have been observed to coexist both within individuals and within families. It is unclear whether clinical reports of comorbid autoimmune diseases represent chance findings or true associations. This systematic review evaluates the current level of evidence on the coexistence of selected autoimmune diseases within individuals and families. We reviewed the associations among 4 TH1-associated autoimmune diseases: insulin-dependent diabetes mellitus, autoimmune (Hashimoto) thyroiditis, rheumatoid arthritis, and multiple sclerosis.

METHODS

Studies quantifying the coexistence between the selected diseases, published through March 2004, were identified from Medline and Embase searches. Study eligibility was determined on the basis of preestablished criteria, and relevant data were extracted according to a fixed protocol. We determined the prevalence of comorbid autoimmune disease according to index disease and then compiled summary statistics. Heterogeneity among studies was assessed by exact likelihood ratio tests and Monte Carlo inference.

RESULTS

We found 54 studies that met the eligibility criteria. Of these, 52 studies examined the coexistence of disease within individuals and 9 studies examined within-family associations. The majority of studies were uncontrolled and did not account for confounding factors. There was substantial evidence for heterogeneity among studies. Although inconclusive, the data appear to support an increased prevalence of autoimmune thyroiditis among patients with rheumatoid arthritis and those with insulin-dependent diabetes mellitus, and an inverse association between rheumatoid arthritis and multiple sclerosis.

CONCLUSIONS

Although the available evidence does not permit firm conclusions regarding comorbidities among the selected autoimmune diseases, results are sufficiently suggestive to warrant further study.