Introduction

Systemic sclerosis (SSc), also known as scleroderma, is a remarkably distinctive disorder with dramatic thickening of the skin accompanied by changes in the pigmentation of the affected skin (vitiligo and melanosis), secondary loss of epidermal sweat, sebaceous glands and hair follicles. Patients with SSc frequently develop a characteristic appearance of their facies -- pursing of their lips and a loss of skin folds -- together with contracture of their joints. Fibrosis of internal organs can lead to a loss of bowel motility with dysphagia, malabsorption and constipation, to pulmonary fibrosis and to restrictive cardiomyopathy.

In addition to the increased collagen production, there is an arterial and small vessel vasculopathy in SSc. This is manifested by telangiectasias, by Raynaud's phenomenon, by necrotizing and proliferative arteriolitis of the kidney leading to renal insufficiency and accelerated hypertension as well as by proliferative endarteritis of the pulmonary circulation leading to primary pulmonary hypertension.

Features of immune dysregulation in the form of autoantibodies are seen in nearly all patients with SSc. In those patients with limited SSc, often referred to as having the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias), the predominant autoantibodies are directed at centromeric antigens. In contrast, the more generalized form of the disease is characterized by the presence of autoantibodies directed at nucleolar antigens (RNA polymerases), a nuclear enzyme (topoisomerase 1) or nuclear molecules involved in the processing of messenger RNA (U1 RNP).

The clinical and serological features of systemic sclerosis are well described in most current rheumatology texts. I like the chapter by Smith and LeRoy in Rheumatology edited by Klippel and Dieppe.(1)

Etiology -- Two New Hypotheses

Immune Dysregulation

While the diagnosis of SSc can often be made easily on the clinical appearance of the patient, the etiology of the disorder is not yet understood. Recently, two very original hypotheses have been postulated as possible partial explanations for the pathogenesis of SSc. The first hypothesis is based on the observation that chronic graft versus host disease (CGVHD) resembles SSc in many of its clinical and immunologic manifestations, including the production of anti-topoisomerase antibodies in some patients, and that the majority of patients with SSc are women in the late or post child bearing age. Nelson et al (2) have proposed that progenitor immune fetal cells, which are known to cross the placenta and transiently enter the maternal circulation, persist as micro chimeric transplants in patients who develop SSc. These cells eventually provoke an immune dysregulation, leading to a form of CGVHD. Artlett et al have recently reported testing this hypothesis in a group of patients with Ssc.(3) They found evidence of persistent male DNA in the circulating blood many years after the delivery of a male infant in many patients with SSc but not in a group of age matched women with a comparable number of male children. Furthermore, they found that SSc mothers were much more likely to have had a child whose Class II HLA type was compatible with that of the mother (that is, would not be rejected by allogeneic immune responses) than were control women matched for age and number of children. The authors suggest that aborted pregnancies, transfusion of blood products or persistence of transplacental maternal cells in fetuses may account for SSc occurring in nulliparous women and men.

Latent HCMV Infection

The other hypothesis, suggested by Pandey and LeRoy,(4) is that latent infection with human cytomegalovirus (HCMV) may be involved in the pathogenesis of SSc. They point out that HCMV has a predilection for infecting human endothelial cells and activating fibroblasts with up-regulation of the production of extracellular matrix proteins including collagen. The HCMV can persist in human cells in a latent state through a number of molecular mechanisms that allow the virus to escape elimination by cytotoxic T lymphocytes and natural killer lymphocytes. Furthermore, HCMV infection is strongly implicated in the pathogenesis of CGVHD and allograft rejection -- conditions that mimic many of the features of SSc. While there is some evidence of an increased frequency of antibodies to HCMV in patients with SSc, as well as other connective tissue diseases, direct and compelling evidence of latent infection with HCMV in patients with SSc awaits further study.