Rheumatology Advance Access originally published online on May 22, 2008
Rheumatology 2008 47(7):1105-1106; doi:10.1093/rheumatology/ken178
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Systemic lupus erythematosus and Franklin's disease: when the somatic mutation mechanism makes a mistake
1Department of Hematology, 2Department of Clinical Biochemistry, University Clinic, University of Navarra, Pamplona, Spain and 3Department of Immunology and Rheumatology, National Institute of Medical Sciences and Nutrition Salvador Zubiran, México City, México
Correspondence to: C. Panizo, Department of Hematology, University Clinic, University of Navarra, Pamplona, Spain. E-mail: cpanizo{at}unav.es
SIR, SLE is an autoimmune disease characterized by immune-mediated attacks against the body's own tissues. The aetiology of the disease remains unknown. Essentially, the fundamental rules of tolerance are violated and autoreactive B- and T-cell clones cooperate, proliferate and lead to the production of pathogenic auto-antibodies [1]. Heavy-chain diseases are rare B-cell lymphoplasmacytic proliferative disorders characterized by the production of truncated monoclonal immunoglobulins lacking light chains [2]. Patients with 
-heavy chain disease (Franklin's disease) frequently develop an associated autoimmune disorder [3], which usually precedes the onset of -heavy chain disease by many years. In this report, a case of SLE complicated by Franklin's disease is described.
A 59-yr-old woman diagnosed with SLE 17 yrs ago (arthritis, oral ulcers, pleural effusion, ANAs and anti-DNA antibodies) was admitted to our hospital in October 2007 with progressive fatigue, weakness, weight loss (7 kg), anorexia, vomiting, dyspepsia and abdominal pain in the month prior to admission. Physical examination revealed a mass in the right flank. The patient was in treatment with low doses of prednisone (10 mg/day) and HCQ (200 mg/day).
Blood tests showed anaemia (Hb 11.2 g/dl), normal platelet count and leucopenia (2.9 x 109/l) with lymphopenia (0.5 x 109/l) and mild neutropenia (2.02 x 109/l). A blood smear revealed the presence of lymphopenia. Laboratory tests on admission showed normal bilirubin, liver enzymes and creatinine levels. Increased titres of ANAs (1/1280) and elevated serum levels of β2-microglobulin (6400 µg/l) and LDH (466 UI/l) were detected. Gammaglobulin quantitation was IgG 2470 mg/dl, IgA 133 mg/dl, IgM 45 mg/dl and IgD 4 UI/l. Serum electrophoresis (SPEP) and immunofixation revealed a monoclonal -spike of 0.85 g/dl (-heavy chain) (Fig. 1A) A 24-h urine specimen contained 1.43 g of protein with a -heavy chain spike. The abdominal ultrasound showed a retroperitoneal large mass confirmed by CT scan (17.5 x 11.3 cm). A laparoscopy biopsy was performed. With conventional haematoxylin–eosin stain, the mass showed a dense neoplastic lymphoplasmacytic infiltrate. The neoplastic cells were immunoreactive for CD138, CD30 and IgG. The cells were negative for CD20, CD10 and CD22. A bone marrow biopsy was also performed. Bone marrow examination showed only moderate increase in plasma cells. The patient was treated with the CHOP regimen (cyclophosphamide, hydroxydaunomicin, vincristin and prednisone) with a partial response after three cycles. A CT scan of the abdomen showed a significant reduction of the mass (7.6 x 5.5 cm) and PET showed a discrete metabolic activity with a standardized uptake values (SUVmax) = 2.58 in the area of residual mass. However, the patient still has persistence of -heavy chain in immunoelectrophoresis in blood and urine without any symptoms.
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- and 
-light chains. Immunofixation was performed on a Sebia system with Hydragel 4 IF gels.Franklin's disease is a lymphoplasmacytic B-cell neoplasia characterized by the production of monoclonal immunoglobulins, which have the immunochemical characteristic of truncated heavy chain without associated light chain. The diagnosis of a lymphoplasmacytic B-cell neoplasia and autoimmune disorder has been reported in 91% of patients with
-heavy chain disease [2]. Coexistence of SLE and Franklin's disease could be explained as a result of somatic hypermutation failure in both diseases. Within germinal centres (GCs), naïve B cells undergo activation, proliferation, somatic hypermutation of rearranged V regions genes, isotype switching and subsequent positive and/or negative selection by antigen. However, GC exclusion of autoreactive B-cells is defective in SLE and the existence of a defective check point in the maintenance of peripheral B-cell tolerance appears to be specific to patients with SLE [4]. This is important, because some autoreactive B cells may initiate GC reactions and autoreactivity increases de novo in the GC through somatic mutations. Moreover, in patients with active SLE, a marked B-cell lymphopenia that affects naïve B cells leads to a relative predominance of memory B cells with multiple somatic mutations [5]. Somatic mutations are introduced at a high rate in the GC and are involved usually in single nucleotide exchanges. However, deletions and insertions may also occur. The involvement of the hypermutation machinery in deletions and insertions seems to be the main cause for the generation of heavy chain disease proteins [6]. Summarizing, we support the idea that both SLE autoimmunity and the generation of aberrant heavy chains in Franklin's disease appear to be generated by somatic hypermutation and could explain this rare association.
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The authors would like to thank Dr José Angel Martinez-Climent for helpful discussion.
Disclosure statement: The authors have declared no conflicts of interest.
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[Abstract/Free Full Text] - Goossens T, Klein U, Kuppers R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc Natl Acad Sci USA (1998) 95:2463–8.
[Abstract/Free Full Text]
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