What is Heavy Chain Disease?
Heavy chain diseases are quite rare diseases in which a large number of modified heavy chains of immunoglobulins of a monoclonal nature are excreted in the urine (the CH1 region is absent, the Fc fragment is normal): in the case of malignant lymphoma, gamma chains, and in the case of lymphoma abdominal localization lymphoplasmacytic infiltration of the small intestine – alpha chains. The amino acid sequence of the N-terminal region of these heavy chains is unchanged, but in the central part of the chain there is a deletion, an exciting part of the variable domain and most of the C (H) 1-domain. Thus, there are no structures in the molecules necessary for connection with light chains.
These diseases are from the group of paraproteinemic hemoblastosis. It is characterized by proliferation of plasma cells producing immunoglobulin heavy chains. This group of diseases includes several rare lymphoplasmacytic tumors secreting abnormal heavy chains of immunoglobulins with a normal Fc fragment and a shortened Fd fragment.
Diseases of heavy chains are rare diseases; only about 50 well-documented cases have been published, among which there are diseases of the heavy chains of all IgG subclasses; the disease occurs mainly in men younger than 40 years and in children of different races.
A-heavy chain disease, more common than a-heavy chain disease, was first detected among residents of the Mediterranean basin and described under the name “Mediterranean lymphoma.” The intestinal form of the a-heavy chain disease is found in North Africa, in the Middle and Near East, in southern Italy, in the basin of the Mediterranean. It is registered, as a rule, in regions with a high incidence of intestinal infections, which, creating conditions for increased antigenic stimulation, may play a primary role in the development of the disease.
Causes of Heavy Chain Disease
To explain the pathogenesis of the disease of heavy chains, a hypothesis was proposed for a gene that controls the formation of one or more segments of heavy chains, when cells formed light chains, but could not connect them to heavy ones; according to another hypothesis, the lesion of factors controlling 2 genes is important (for cases without light chain formation).
Abnormal proteins in heavy chain diseases are formed in abnormal plasma cells. The emergence of only heavy chains is explained by a gene mutation with a possible deletion of the gene that determines the synthesis of heavy chains. Very rarely mu heavy chains are found in the urine. Only the use of specific antisera allows to detect heavy chains and prove their isolation from light chains. Heavy chains are homogeneous, always refer to only one of the known subclasses of immunoglobulins. Heavy chains a and mu have a high capacity for polymerization, their molecular weight is less than normal analogues.
It is believed that this defect is due to the wrong combination of genes in the V and C regions. There are 4 types of abnormal heavy chains of immunoglobulins – gamma, alpha, mu and delta. Abnormal heavy chains are bound by antibodies to native immunoglobulins and are not bound to antibodies to light chains of immunoglobulins.
Pathogenesis During Heavy Chain Diseases
Separate diseases of heavy chains form depending on the type of heavy chains. Diseases of heavy chains are clinically encountered with a rapidly progressing course and with a slow development of characteristic symptoms.
Symptoms of Diseases Heavy Chains
Clinical manifestations depend on the isotype of heavy chains.
A disease of heavy gamma chains, a disease of heavy alpha chains and a disease of heavy mu chains are known, a single case of a disease of heavy delta chains is described, a disease of heavy epsilon chains is not described. Genetic defects have been identified in the tumor cells, which can cause the secretion of abnormal chains. According to the clinical picture, the diseases of this group are similar to lymphomas. Physical examination revealed an increase in lymph nodes and hepatosplenomegaly, in a study of the bone marrow – diffuse infiltration with lymphocytes, plasma cells, eosinophils and macrophages. On B-lymphocytes, surface immunoglobulins are absent. The causes of diseases in this group are unknown.
Heavy chain disease is often referred to in the literature as “Franklin’s disease.” Its clinical picture is characterized by rapid progression, hyperplasia of peripheral, mediastinal, retroperitoneal lymph nodes. Valdeyerevo ring in the form of a tumor of tonsils, uvula, palate, as well as liver, spleen, thyroid gland are affected. Fever is often caused by infectious complications, often the cause of death. Histologically detect proliferation of lymphoid cells of varying degrees of maturity, plasma cell infiltrates.
The disease of a-heavy chains is characterized by chronic diarrhea, weight loss, pale skin, edema, impaired calcium-phosphorus metabolism, alopecia, migratory arthralgia, episodic fever, paroxysmal abdominal pain, and vomiting. In the advanced stage of the disease, hyperplasia of the mesenteric lymph nodes is noted, and sometimes hepatomegaly. Impaired absorption is expressed in hypocalcemia, hypocalciuria, hypophosphatemia, increased levels of alkaline phosphatases, decreased levels of lipids, prothrombin, and blood sugar.
With a disease of mu-heavy chains for a long time, patients do not have an increase in peripheral lymph nodes, the liver and spleen grow quite early, amyloidosis and pathological fractures occur. Lymphocytosis and plasma cells with pathological vacuolization are found in the bone marrow.
Diagnosing Heavy Disease Diseases
The diagnosis is based on the identification of monoclonal immunoglobulin, containing only a fragment of the heavy chain of one of the main classes of immunoglobulins. This is only possible with an immunochemical examination of blood and / or urine using heavy chain antisera.
Hemogram studies reveal anemia, in 1/3 of patients – leukopenia, usually caused by granulocytopenia, atypical lymphoid and plasma cells, sometimes eosinophilia, in half of the patients – thrombocytopenia. ESR is often elevated. There is hyperuricemia. In the myelogram, the content of plasma cells and (or) lymphocytes and reticular cells is usually increased.
The diagnosis of the disease in heavy chains is based on the detection of abnormal protein in serum and / or urine. The content of total protein in serum is usually normal or reduced.
Heavy chain disease often occurs in individuals who have previously suffered from autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, pulmonary fibrosis, myasthenia, thyroiditis, hemolytic anemia. In other patients, polyclonal gammopathy precedes the detection of the M-component.
Radiographically detect changes in the mucous membrane of the stomach and large intestine (disorganization of the folds of the mucous membrane with alternating zones of narrowing and expansion). Histological examination of the entire mucosa of the small intestine reveals diffuse proliferation of lymphocytes and plasma cells with signs of atypism, villous atrophy, a decrease in crypts. Epithelial cells are not damaged. In the hyperplastic mesenteric lymph nodes, a pattern of proliferation of lympho-or reticulosarcoma plasma cells is revealed. There are single descriptions of the disease with bone marrow infiltration. The disease progresses rapidly, and cachexia, abdominal and other complications are the immediate cause of death.
Treating Heavy Disease Diseases
Doctors currently do not yet have sufficiently effective treatments for diseases of heavy chains. Local irradiation of the spleen and lymph nodes gives a quick but short-term improvement. Alkylating agents are also not very effective. In some patients, a favorable response to prednisone or vincristine was observed. Attempts are being made to combined chemotherapy according to the principles of treatment of chronic lymphocytic leukemia, malignant non-Hodgkin’s lymphomas. In the presence of immunodeficiency syndrome, the appointment of immunocorrective agents is justified. Described cases of treatment in the disease and heavy chains as a result of prolonged use of antibiotics. In recent years, plasmapheresis has been used for heavy chain diseases.