Autoimmune diseases are thought to be initiated by exposures to foreign antigens that cross-react with endogenous molecules. Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, we hypothesized that the “foreign” antigens in this autoimmune disease are encoded by somatically mutated genes in the patients’ incipient cancers. Studying cancers from scleroderma patients, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to RPC1 but not in eight patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma and provide support for the idea that acquired immunity helps to control naturally occurring cancers.

Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. 1,2 Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. 3-7 Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. 8,9 In particular tumor necrosis factor ␣ (TNF␣), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. 10,11 Moreover, TNF␣ gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. 12, 13 We studied the distribution of −G308A TNF␣ gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects TNF␣ plasma levels. 14-18 Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of TNF␣ as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component. Molecular Psychiatry (2001) 6, 79-82.

SynopsisMany conditions presenting with clinical hard skin and tissue fibrosis can be confused with systemic sclerosis (scleroderma). These disorders have very diverse etiologies and often an unclear pathogenetic mechanism. Distinct clinical characteristics, skin histology and disease associations may allow to distinguish these conditions from scleroderma and from each other. A prompt diagnosis is important to spare the patients from ineffective treatments and inadequate management. In this review, we highlighted nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), eosinophilic fasciitis (Shulman's syndrome), scleromyxedema and scleredema. These are often detected in the primary care setting and referred to rheumatologists for further evaluation. Rheumatologists must be able to promptly recognize them to provide valuable prognostic information and appropriate treatment options for affected patients.

No abstract