Alpha Heavy Chain Research Articles

Hodgkin's disease: an immunohistochemical and histological study.

The distribution of immunoglobulin (Ig) in Hodgkin's tissue has been demonstrated in paraffin and cryostat sections by the unlabelled antibody peroxidase-antiperoxidase (PAP) method and the two-stage fluorescein isothiocyanate (FITC)-based technique. The morphology and histogenesis of the Reed-Sternberg (RS) and Hodgkin (HD) cells has been studied with the metalophil method of Marshall (1948) and this revealed a population of dendritic histiocytes which corresponded in number, sizes and distribution to the RS and HD cells in adjacent sections stained by haematoxylin and eosin. The largest RS cells, however, appeared to be non-dendritic. A notable feature of Hodgkin's tissue was the tendency for the dendritic cells to form "nodules", in combination with a population of small lymphocytes. The PAP technique reveals Ig in the form of mu and delta heavy chains, as well as kappa and lambda light chains, in close association with and probably on the surface of a high proportion of these lymphocytes, suggesting that they are immature B cells. Similar reactions were given by the mantle of lymphocytes of surviving normal lymphoid follicles, and metalophil dendritic histiocytes were also demonstrated within the mantle and subjacent part of the germinal centre. Numerous immunocytes containing Ig were present in all lesions; in the majority of cases, more cells contained gamma than alpha or mu heavy chains, although in these cases alpha-positive cells outnumbered those containing gamma or mu heavy chains. In two-thirds of the cases, one-third of the RS cells contained cytoplasmic immunoglobulin. This was exclusively gamma heavy, although both light chains were present. In about half the cases a minority of the HD cells contained gamma chain. The results suggest that HD and RS cells are dendritic histiocytes of the type normally found in the lymphoid follicles and that their tendency to form nodules in assoication with B lymphocytes is a manifestatin of this origin. It is suggested that the presence of Ig most probably results from absorption of antigen-antibody complexes on the cell surface.

Immunodiagnosis of alpha heavy chain protein (αHCP) in immunoproliferative small intestinal disease (IPSID)

Immunodiagnosis of alpha heavy chain protein (αHCP) in immunoproliferative small intestinal disease (IPSID)

“Mediterranean abdominal lymphoma” or immunoproliferative small intestinal disease.Part II: Pathological aspects

The pathology of 25 cases of Mediterranean abdominal lymphoma, better designated as immunoproliferative small intestinal disease (IPSID), are reported from the American University of Beirut Hospital. The series includes nine cases with documented alpha heavy chain disease (alpha-HCD). The disease is characterized by the presence of a diffuse and compact bandlike lymphoplasmacytic infiltration of the proximal small intestinal mucosa. The presence of a concomitant malignant lymphoma in the intestine and/or mesenteric lymph nodes, and of alpha-heavy protein in the serum is commonly encountered. Two histopathologic variants of IPSID are present. The first is characterized by the diffuse infiltration of the mucosa, at sites away from tumoral masses, by either pure plasmacytic infiltration, or mixed lymphoplasmacytic infiltration. This variety is associated with the immunoblastic sarcoma type of malignant lymphoma, and with alpha chain disease (alpha-HCD). The second variant is characterized by a diffuse follicular lymphoid hyperplasia pattern in the small intestinal mucosa. The associated malignant lymphoma is diffuse and undifferentiated often having a starry-sky pattern. This variety is not associated with alpha-HCD. Both histologic variants share the same clinical antecedents. In five patients, mesenteric lymph nodes harbored immunoblastic sarcoma while the intestinal mucosae of the same patients were involved with a benign appearing lymphoplasmacytic infiltration. This finding stresses the need for staging laparatomy. Three patients, with alpha-HCD, had peripheral lymph node involvement with immunoblastic sarcoma. The disease apparently evolves in two stages: an immunoproliferative phase, probably reversible, and a later development of malignant lymphoma. The term immunoproliferative small intestinal disease accurately describes the nature of the entity.

New presentation of alpha heavy chain disease: North American polypoid gastrointestinal lymphoma.Clinical and cellular studies

Alpha Heavy Chain Disease has generally been described in the Mediterranean area in young people with a diffuse gastrointestinal lymphoma and malabsorption. We describe a patient from the United States with polypoid lymphoma of the gastrointestinal tract and a prolonged clinical course, who had the characteristic alpha heavy chain disease protein. He did not have malabsorption, and the gastrointestinal tract, though containing multiple discrete lymphomatous polyps had little plasmacytic reaction. Lymphosarcoma cell leukemia developed late in the course and the malignant cells had the characteristics of B lymphocytes but did not contain alpha heavy chains. The data support the contention that the lymphoma in this form of alpha heavy chain disease may involve B lymphocytes but that the abnormal protein may be produced by other cells. Polypoid varieties of gastrointestinal lymphoma in North America must now be considered part of the spectrum of alpha heavy chain disease and the diagnostic protein searched for diligently.

“Mediterranean abdominal lymphoma,” or immunoproliferative small intestinal disease.Part I: Clinical aspects

The pathology of 25 cases of Mediterranean abdominal lymphoma, better designated as immunoproliferative small intestinal disease (IPSID), are reported from the American University of Beirut Hospital. The series includes nine cases with documented alpha heavy chain disease (alpha-HCD). The disease is characterized by the presence of a diffuse and compact bandlike lymphoplasmacytic infiltration of the proximal small intestinal mucosa. The presence of a concomitant malignant lymphoma in the intestine and/or mesenteric lymph nodes, and of alpha-heavy protein in the serum is commonly encountered. Two histopathologic variants of IPSID are present. The first is characterized by the diffuse infiltration of the mucosa, at sites away from tumoral masses, by either pure plasmacytic infiltration, or mixed lymphoplasmacytic infiltration. This variety is associated with the immunoblastic sarcoma type of malignant lymphoma, and with alpha chain disease (alpha-HCD). The second variant is characterized by a diffuse follicular lymphoid hyperplasia pattern in the small intestinal mucosa. The associated malignant lymphoma is diffuse and undifferentiated often having a starry-sky pattern. This variety is not associated with alpha-HCD. Both histologic variants share the same clinical antecedents. In five patients, mesenteric lymph nodes harbored immunoblastic sarcoma while the intestinal mucosae of the same patients were involved with a benign appearing lymphoplasmacytic infiltration. This finding stresses the need for staging laparatomy. Three patients, with alpha-HCD, had peripheral lymph node involvement with immunoblastic sarcoma. The disease apparently evolves in two stages: an immunoproliferative phase, probably reversible, and a later development of malignant lymphoma. The term immunoproliferative small intestinal disease accurately describes the nature of the entity.

Location and structural significance of the oligosaccharides in human Ig-A1 and IgA2 immunoglobulins.

The location, number, and kinds of oligosaccharides in human IgA1 and IgA2 immunoglobulins have been determined by amino acid sequence analysis of the alpha heavy chains. Both A2m allotypes of the alpha2 chain of IgA2 have two GlcN oligosaccharides that are absent in the alpha1 chain, but they lack GalN. The A2m(2) allotype has a fifth GlcN oligosaccharide. The alpha chains of IgA proteins also have subclass-specific and allotype-specific differences in amino acid sequence. Although other classes of human immunoglobulins differ in the number and kind of oligosaccharides, the sites are often homologous and are related to the immunoglobulin domain structure. Evolutionary preservation of the tripeptide acceptor sequence for GlcN probably indicates both a structural and biological role for carbohydrate.

Mediterranean lymphomas with alpha heavy chain monoclonal gammopathy.

Nine cases of Mediterranean lymphoma with alpha heavy chain disease are described. All patients were young, aged between 11 and 22 years. Neither sex predominated in the series. The clinical presentation of the disease was either gastrointestinal, with chronic diarrhea and malabsorption, or neoplastic, with tumors frequently associated with either obstructive or perforative complications. Finger clubbing and retardation of physical growth (height and weight) and secondary sexual maturation were usually evident. The laboratory manifestations of the malabsorption syndrome were scant and generally not specific. The intestinal lesions predominated in the beginning of the small bowel, and their gross appearance varied from one case to another: diffuse thickening of the intestinal wall, alone or associated with tumors, or isolated segmentary tumors. Massive mesenteric lymph node enlargement was present in all cases; in some cases hepatic, splenic, or extra-abdominal lymph node spread was noted. Histologically, these lesions demonstrated a varied cellular morphology, but seemed to belong constantly to the B-lymphocytic line. The secretion and excretion by these cells of an abnormal IgA (devoid of light chains), which was revealed by immunoelectrophorectic study of the patients' sera, was the main biochemical abnormality of the disease. This disease presents several problems: 1) its relationship with other intestinal lymphomas; 2) the nature and the degree of malignancy of the intestinal cellular infiltrates; and 3) its identification as a clinicopathologic entity, with the possibility that infectious and genetic factors are significant in its etiology and pathogenesis.

Complete covalent structure of a human IgA1 immunoglobulin.

The complete covalent structure has been determined for a human myeloma IgA1 immunoglobulin. This protein has unique features in the amino acid sequence and disulfide bridge structure of the variable (V) and constant (C) regions of both the alpha heavy and the lambda light chains, and in the number and loci of oligosaccharides. Whereas C region domains of heavy chains have evolved independently over eons, recent isotypic variations have occured in lambda light chains and possibly in alpha heavy chains.

The evolution of alpha heavy chain disease

Two patients with alpha heavy chain disease are described. In the first patient, treatment with cyclophosphamide, prednisone and doxycycline was associated with a 28 month-long remission and the disappearance of the paraprotein and lymphoplasmocytic infiltration of the intestine. Shortly afterwards, a retroperitoneal immunoblastic lymphoma was found associated with an immunoglobulin G-kappa-paraproteinemia, and gamma heavy and kappa-light chains in the urine; the intestinal biopsy specimen was normal. In the other patient, the alpha chain only appeared two years after the malabsorption syndrome. The fact that in the first, apparently cured patient, a tumor of different anatomic site and secretory capacity appeared, suggests the existence of a B-cell neoplasia of different clone from that which gave rise to the original disease. In the second patient, it is probable that only the increase in the mass of neoplastic cells led to the detection of the protein abnormality, or alternatively the antigenic-oncogenic stimulus led to the abnormal secretion only after two years.

The evolution of alpha heavy chain disease : Guardia J, Rubiés-Prat J, Gallart MT, Moragas A, Martínez-Vásquez JM, Bacardi R, Vilaseca J: Am J Med 60: 596–602, 1976

The evolution of alpha heavy chain disease : Guardia J, Rubiés-Prat J, Gallart MT, Moragas A, Martínez-Vásquez JM, Bacardi R, Vilaseca J: Am J Med 60: 596–602, 1976

Fragments of immunoglobulins in human faeces.

Fab-fragments of IgG were easily demonstrated in extracts of faeces from healthy infants and children. Employing immunoelectrophoresis with antisera to whole human serum and to Fab-fragments of IgG, a marked precipitation line, likely to represent such fragments, was evident in the cathodal or gamma-region. Usually no precipitate was formed with antisera specific for gamma-heavy chains or Fc-fragments of IgG. Presumably IgG in the gut is partially destroyed before being excreted with faeces. Results of immunoelectrophoresis, gel filtration as well as polyacrylamide gel electrophoresis, using antisera to alpha-heavy chains, indicated the presence of fragments of IgA in some faecal extracts. Fragments of IgA could not be demonstrated in IgA-deficient patients, and no fragments of either class, or only traces of Fab-fragments of IgG, were found in agammaglobulinaemic patients. No antibody activity against rabbit erythrocytes was found in gel filtrations containing such fragments; any reaction was not observed either in the direct agglutination test or in a modified antiglobulin test.

Distribution of immunoglobulin-containing cells in human bone marrow and lymphoid tissues.

Cell suspensions of human bone marrow, spleen, lymph nodes and palatine tonsils have been investigated for the presence of intracellular immunoglobulins by a direct immunofluorescence technique, using monospecific antisera against human Ig heavy chains alpha, mu and gamma and light chains kappa and lambda. Serum Ig levels were determined and the number of positive cells was compared with the concentration and calculated synthetic rate of serum Ig in each individual. The 28 patients studied covered a wide range of diagnoses and included those with normal as well as pathologically decreased or increased serum Ig levels. There was a high correlation between the calculated synthetic rate of each Ig class and the percentage of cells positive for the same Ig class in the bone marrow but not in the spleen, lymph nodes or tonsils. The Ig-containing cells constituted a much larger proportion of the total lymphoid cell population in the bone marrow than in the peripheral lymphoid organs. The estimated total number of Ig-containing cells was also much larger in the bone marrow than in the other organs investigated. It is concluded that in man the bone marrow is the major site of serum Ig synthesis and that the average synthetic rate per cell is the same regardless which of the three major Ig classes is produced. The role played by different lymphoid organs in humoral immunity is discussed in the light of the present results and reported data regarding lymphocyte and plasma cell kinetics in mammals.

Immune modulation and disease patterns in population groups

A hypothesis which explains disease prevalence among different socio-economic groups following early infantile modulation of cell-mediated immunity by infection and nutrition related stress is presented. Wealthy populations living under highly hygienic circumstances can develop their cell-mediated immunity to genetic expectation while their humoral systems remains unstimulated. Primitive populations protect the infant's immune development by breast feeding and suffer from temporary cell-mediated immune deficiencies due to intercurrent infectious disease and famine later on. Intermediary populations harbour a small percentage of people, whose cell-mediated immune system has been permanently damaged by infection in early childhood, leading to a high incidence of diseases linked to cell-mediated immune deficiency. The possible cocarcinogenesis of the cell-mediated immune deficiency following repeated gastroenteritis and persistent stimulation of B cells, leading to alpha heavy chain disease and primary intestinal lymphoma, or due to falciparum malaria in newborns and its impact on the EB virus genome in development of Burkitt's lymphoma, are discussed.

Alpha heavy chain disease.

Alpha heavy chain disease.

Pattern of immunoglobulin synthesis and assembly in a human-mouse somatic cell hybrid clone.

Fusion of human peripheral blood lymphocytes, not forming detectable immunoglobulins, with mouse myeloma cells (TEPC-15), secreting mouse immunoglobulin A with known antibody activity, yielded a somatic cell hybrid clone that secreted both human and mouse immunoglobulins. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that human gamma, alpha, and light chains, as well as mouse alpha and light chains, were formed by the hybrid cells. To determine whether individual antibody molecules with both human and mouse components were secreted, medium from the hybrid cells was precipitated first with antibody against mouse immunoglobulin produced in rabbit, reduced, and alkylated, and then reprecipitated with antibody against human immunoglobulin produced in rabbit. Human gamma, alpha, and light chains were detected after electrophoresis of the immunoprecipitates on sodium dodecyl sulfate-polyacrylamide gels, indicating that antibody molecules containing both human and mouse components were secreted by the hybrid cells. These data indicate that this somatic cell hybrid clone synthesized human gamma and alpha heavy chains and human light chains, as well as mouse alpha heavy chains and mouse light chains. Some of these immunoglobulin components were assembled as hybrid antibody molecules.

An alpha heavy chain abnormality in a child with hypogammaglobulinemia

A new immunoglobulin A abnormality has been found in the serum of a child with hypogammaglobulinemia. The abnormal protein has a sedimentation coefficient of 5.2S and consists of two alpha chains covalently linked to J chain. No light chains could be detected in the protein. The abnormal protein, like the alpha chain disease proteins previously described, belongs to the A1 subclass and reacts with an antiserum specific for free alpha chains.

Immunochemical studies in four cases of alpha chain disease.

Studies of a number of properties of the pathological gammaA-proteins in the first four cases of the recently recognized alpha-chain disease demonstrate that, as in gamma-heavy-chain disease, the abnormal protein is devoid of light chains and represents a portion of the alpha-heavy chain related to the Fc-fragment. In two patients, serum electrophoresis showed a broad abnormal band, whereas in the two others the pathological protein was not noticeable on the electrophoretic pattern. The diagnosis of alpha-chain disease can be established without purification of the protein by immuno-electrophoresis and gel diffusion experiments using selected antisera to gammaA and a reference alpha-chain disease protein. All four proteins belonged to the alpha1-subclass, displayed electrophoretic heterogeneity, and showed a strong tendency to polymerize. The polymers occurred in vivo and were held together both by disulfide bonds and by strong noncovalent forces. Two of the three purified proteins had a very high carbohydrate content. The abnormal protein was always found in concentrated urines in variable but generally low amounts. It was not detected in parotid saliva but was present in significant amounts in jejunal fluid of all four patients. The alpha-chain disease protein was shown to be associated with the secretory piece in external secretions of two patients. The clinicopathological features were strikingly similar in the four patients. All patients were affected with a neoplastic and mostly plasmacytic proliferation involving primarily the whole length of the small intestine and the mesenteric nodes and all exhibited a severe malabsorption syndrome. While Israeli authors have emphasized the frequency of this type of abdominal lymphoma in young Arabs and non-Ashkenazi Jews, two of our patients were Kabyles, one a Syrian Arab, and one an Eurasian. Cellular studies showed that the pathological protein was synthesized by the proliferating cells in the lymphoid tissue of the digestive tract and in the mesenteric nodes, and that there was no detectable light-chain synthesis at the intracellular level.