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The authors report the chance discovery in a man aged 53 years with serum positive rheumatoid arthritis, of gamma 3 heavy chain disease. The originality of this case depended on the absence of any detectable lymphoid proliferation and on the transient character of the pathological protein. Only the course after a long follow up will determine whether there is no incipient lymphoid proliferation and whether the heavy chain disease has disappeared permanently.

Description of a case presenting as an inflammatory polyarthritis. A uterine sarcoma was detected one year later and led to the death of the patient. The abnormal protein belonged to the gammal subclass. Biosynthesis experiments, performed on the marrow plasma cells, showed that light chains were not produced and that the molecular weight of the monomeric unit of the serum protein was slightly smaller than that of the protein secreted in vitro, suggesting the occurrence of a secondary and limited extracellular proteolysis.

A case of gastric lymphoplasmocytoid lymphoma with alpha heavy chains in the serum is reported. The patient was a 20-year-old female who had a gastric lymphomatous ulcer and who died of acute bleeding, with no clinical or radiological signs of small intestine involvement. This seems to be the first reported case of gastrin alpha heavy chain disease.

This group of proliferative diseases of the plasma cell line, in which manifestations of abnormal immunoglobulin production are associated with variable degrees of depressed antibody synthesis, pose fascinating problems crossing many clinical and research disciplines. The present state of diagnosis and clinical management is assessed.

Specific bone lesions are not usually found in heavy chain alpha disease we report a case in which images identical to those seen in Parker and Jackson's sarcoma (bone lymphoma) were found. The malignant lymphomatous nature of the lesion could not be confirmed as a bone biopsy was not made, but its regression under chemotherapy makes the diagnosis almost certain. Indirectly, arguments in favour of this hypothesis can be drawn from the common cellular origin of bone lymphomas and monoclonal gammopathies. Furthermore, it is logical to assume that heavy chain alpha disease, as with most other immuno-proliferative syndromes, can be associated with malignant lymphomatous changes in the skeleton.

The radiologic changes in 1090 cases of lymphoma of the small bowel were analyzed and correlated with the pathologic findings. The material was collected in Iran, a high incidence area for immunoproliferative small bowel disease (IPSID). Of 100 cases of primary intestinal lymphoma associated with IPSID, 48 involved the duodenum and upper jejunum. They were associated with a characteristic spruelike radiologic pattern of the nonlymphomatous segments of the gut, the intensity of which decreased distally. However, the radiologic features of the lymphoma associated with IPSID were identical with those described in other forms of primary small intestinal lymphoma, regardless of histologic type or the presence and absence of alpha-heavy chain secretion.

The first recorded case of a small intestinal lymphoma with alpha heavy chain disease occurring in Hungary is reported. The clinical manifestation of the disease and the focal distribution of mucosal alterations do not fulfill the criteria to make a diagnosis of Mediterranean type lymphoma (MTL) but the lymphomatous segments of the jejunum show the same pathological and immunohistological characteristics as seen in MTL. One of the basic features of MTL, the so called lympho-histiocytic nodules, which have been suspected by previous authors to represent an incipient neoplastic process involving histiocytic cells, is identified as follicular centroblastic/centrocytic malignant lymphoma. The cytogenetical connection between the massive proliferation of abnormal alpha chain producing plasma cells and neoplastic germinal centres is substantiated by direct immunohistological evidence using a combined immunofluorescent and immunoperoxidase technique to detect heavy and light chains within the same cell. The sarcomatous-appearing pleomorphic cell proliferation is interpreted as an anaplastic change in the centroblastic/centrocytic lymphoma. Unequivocal evidence for an abnormal IgA production in this pleomorphic component has not been obtained. Our observations suggest that in alpha heavy chain disease the neoplastic cell population originates in the germinal centres.

A case of alpha-chain disease of the pulmonary type is described in a man presenting with dyspnoea, mottling on chest x-ray picture, and a CO-transfer factor of 36%, suggestive of fibrosing alveolitis. The serum IgA consisted entirely of abnormal alpha chains devoid of light chains. This protein had the unusual property of reacting by immunofluorescence with rat mitochondria but not with human issues or with those of other species. Postmortem examination showed enlarged mediastinal lymph nodes with no evidence of malignancy or fibrosing alveolitis.

Clinical, immunochemical and pathological studies were performed in a 27-year-old male who presented with abdominal pain, the malabsorption syndrome, and marked weight loss. Immunoelectrophoretic studies revealed alpha-heavy chains in the patient's serum, urine and intestinal juice. Treatment with cyclophosphamide and corticosteroids produced an improvement in the patient's condition and he survived for 18 months after the onset of symptoms. Autopsy revealed a malignant lymphoma of mixed histiocytic-lymphocytic type involving mainly the mesenteric lymph nodes, but also affecting the jejunal mucosa, liver, spleen and extraabdominal lymph nodes. This is the first case of abdominal lymphoma with alpha-heavy chain disease to be reported from Yugoslavia.

A 40-year-old man born in Bangladesh developed alpha heavy chain disease whilst a resident in the United Kingdom. An incomplete, low molecular weight alpha heavy chain protein, devoid of light chains was demonstrated in his serum. Clinical remission of his disease was achieved by antibiotics alone.

A 52 year old man presented with multiple myeloma and widespread amyloidosis involving joints, bursae- carpal tunnels, lymph nodes and subcutaneous tissue. Osteolytic bone lesions and pathologic fracture of the neck of the left femur were found. Bone marrow was infiltrated with both plasmacytes and lymphocytes. The majority of plasma cells contained large cytoplasmic vacuoles. Free kappa II type light chains and mu-heavy chain fragment were detected in the serum, and kappa II type Bence Jones protein was found in the urine. The molecular weight of the mu-heavy chain fragment was found to be approximately 50,000 daltons. An immunofluorescence study, using the double labelling technic, showed that the majority of plasmacytes in bone marrow contained both mu and kappa antigenic determinants in the cytoplasm. A review of the 12 previously described patients with mu-heavy chain fragment in the serum showed a variable clinical picture, thus their natural history and therapeutic response are difficult to evaluate at the present time. It seems that mu-heavy chain fragment can be found in a variety of clinical conditions and that mu-heavy chain disease cannot yet be accepted as a separate clinical entity.

The 2 patients have cold agglutinin disease with lymphoid nodules in the bone marrow. A splenectomy was done because of the severity of the hemolytic anemia and because of the increasing splenomegaly. Tumoral nodules with the aspect of lymphoplasmocytic sarcoma or immunocytoma were discovered in the spleen. Those tumors can be considered either as a morphologic aspect of the cold agglutinin disease which is yet considered as a kind of chronic lymphoproliferative syndrom or as the proliferation of an other clone. In this hypothesis, the lymphoplasmocytic sarcoma habe the same signification that the Richter's syndrome in chronic lymphoid leukemia and that the sarcoma appearing in Waldenström's macroglobulinemia or in alpha heavy chain disease.

About one hundred cases of alpha-chain disease have been reported to date from various Mediterranean and Middle-Eastern countries. We report eleven Iranian patients with primary lymphoma of the duodenum and upper small intestine and positive alpha-chain protein in their sera. The clinical, laboratory and pathological findings in these patients are discussed. The initial favourable response of some of these patients to antibiotic treatment is noted. It is concluded that the optimal treatment of alpha-chain disease is not yet well established, and the clinical improvement might not coincide with histological and immunological remission.

We report the association of monoclonal mu-heavy chain and a monoclonal IgG K paraprotein in a patient with systemic lupus erythematosus (SLE). This association and the apparently benign nature of this biclonal gammopathy has not been previously reported.

A patient with evidence at presentation of alpha-heavy chain disease and an immunoblastic lymphoma is presented, who had remained in clinical, histologic, and immunologic remission for more than 12 years following initial radiotherapy and corticosteroids. The suggested management of this condition and its prognosis is discussed.

A patient with lambda Bence-Jones proteinuria, Waldenström's macroglobulinaemia, and Franklin's disease (gamma HCD), but without clinical evidence of a lymphoproliferative disorder, is presented. The serum contained two distinct immunoglobulin abnormalities: a monoclonal immunoglobulin M (IgM) of lambda type, and a protein fragment which was immunologically related to immunoglobulin G (IgG) and devoid of light chain activity. This gamma HCD protein belongs to the gamma 3 subclass with a molecular weight of approximately 60,000 daltons. The urine contained a Bence-Jones lambda protein as well as the gamma HCD fragment. The two paraproteins were probably secreted by two different malignant clones. Ultrastructural study revealed pathological vacuolated plasma cells of a sort that has hitherto been principally described in association with micron HCD. The mechanism of the intracellular storage of pathological immunoglobulins is discussed in the light of the ultrastructural study.

Making the diagnosis of alpha-chain disease in the laboratory is difficult. Immunologic and structural characteristics of the abnormal protein were shown in results of cellular studies. There are clinicopathological features associated with the protein abnormality. The peculiar geographic origin of patients affected with alpha-chain disease and the possible reversibility of the hyperplastic process at its early stage lead to some considerations of cause.

On the basis of microscopic evaluation of bone marrow aspirate, multiple myeloma and secondary marrow hypoplasia was diagnosed in a 7-year-old female Doberman Pinscher. Electrophoresis, radial gel diffusion, and immunoaffinity chromatography indicated that serum and urine specimens contained alpha immunoglobulins without kappa or lambda light chains. Whole immunoglobulins (Ig) A, IgG, or IgM were not found. The dog was treated with prednisolone and melphalan for 11 weeks, after which time the owner refused examination and treatment of the dog.

Ten cases of primary upper small-intestinal lymphoma associated with alpha-chain protein in serum were discovered in a prospective study of the sera of patients with immunoproliferative small-intestinal disease (IPSID). Patients were mostly young males presenting with abdominal pain, weight loss, and diarrhea and showing laboratory evidence of carbohydrate, fat, and vitamin B12 malabsorption and hypoalbuminemia. The more frequently encountered pathologic abnormality was a diffusely nodular jejunal mucosa produced by a plasmacytic infiltrate of variable cell maturity involving a varible depth of small bowel wall with or without involvement of the mesenteric or para-aortic-lymph node complex and, in one instance, the liver. A less frequent picture included circumferential ulcerative and constrictive transmural tumors of the upper small intestine produced by a malignant lymphoma with involvement of abdominal lymph nodes. Small-intestinal surface epithelial abnormalities, a dense mantle of mature plasma cells overlying the lymphoma, a pronounced follicular lymphoid hyperplasia adjacent to and at distances from the lymphoma were other features of note in our IPSID cases associated with alpha-chain protein.

The first two cases of alpha chain disease from Central Africa are reported from Nigeria. Both patients show the classical features of the disease with diffuse involvement of the small bowel and malabsorption. The patients were lost to follow-up but died soon after diagnosis.

A patient (Mia) with a monoclonal IgM(kappa) cryoglobulin (cryo IgM) developed additional heavy chain disease proteins of the gamma3 subclass 8 years later. Biochemical studies of the cryo IgM indicated that the heavy chain was VHI, but the NH2-terminal amino acid sequence of the light chain did not permit a definite assignment of its Vkappa subgroup. Two major fragments of the gamma3 chain were distinguishable by electrophoresis in sodium dodecyl sulfate polyacrylamide gel. The smaller component (designated Mia F) had a molecular weight of approximately 30 000 and the larger component (designated Mia S) 35 000. Both fragments had G3m(21) and G3m(27) allotypic determinants. These data and the NH2-terminal amino acid sequence of the gamma chain fragments suggested that Mia S consists of the major part of the gamma3 hinge region plus the CH2 and CH3 domains of the gamma3 chain, whereas Mia F may be derived from the former as a result of postsynthetic cleavage. The partial amino acid sequence of the Mia S fragment is homologous to the hinge region amino acid sequence of human gamma3 chains reported in the literature, with only one amino acid difference out of the 11 residues compared. This difference may represent an allotypic difference within the gamma3 subclass. Alternatively, the production of Mia S may have resulted from the accidental derepression of a "silent" constant region gene not expressed in normal individuals.