Brain membrane protein band 3 performs the same functions as erythrocyte band 3.

Clinically healthy humans as well as patients suffering from various autoimmune diseases produce natural antibodies against a variety of self-components. Such antibodies have been proposed to carry out a physiologic role in maintaining the integrity of self, as well as potentially destructive roles in the generation of autoimmune diseases. Because human autoantigens, particularly membrane proteins, are usually present in extremely small amounts, it is generally impossible to obtain enough to carry out a detailed characterization of the antibodies or the antigenic determinants recognized. To circumvent this difficulty, we developed synthetic autoantigens predicted from the gene sequence of two functionally critical membrane proteins; the band 3 anion transport protein which is found on all cells, and the T-cell receptor (β chain) which is the antigen-specific receptor on thymus-derived lymphocytes. We have investigated the natural human IgM and IgG antibody responses to peptides selected on the basis of predicted molecular surface exposure and previously known antigenicity, and correlate levels of binding with changes in age and by comparison with autoimmune diseases. We report that the IgM response to synthetic autoantigens tends to be higher than that of IgG molecules, but significant IgG binding occurs to some peptides. This situation is particularly noticeable in comparison of rheumatoid arthritis patients with normal individuals. Distinct peptide portions of individual molecules are recognized differently by the autochthonous immune system as manifested by age dependence of the response and differential levels of IgM and IgG activity. The synthetic autoantigens that tend to generate the highest amounts of natural antibody are those that are either exposed on the surface of the cell (band 3 peptides) or are exposed in the predicted 3-dimensional folding of the molecule (T-cell receptor β peptides). Rheumatoid arthritis patients tend to give higher IgM reactivities to both band 3 and Tcr β peptides than do normals, with this effect being less pronounced in the distinct autoimmune disease systemic lupus erythematosus. Studies of normal humans ranging in age from 20 to 90 years suggest two major patterns for the IgM natural antibody response to synthetic peptides giving high response. The first is that the level of IgM reactivity is high early in life and remains high throughout. The second pattern is one in which the reaction is high in younger individuals, but diminishes substantially in the latter decades of life. Although there is substantial variation in the IgG autoantibody responses, which most probably are strongly dependent upon T-cell help, the overall pattern is for these to be low early in life, and to increase with increasing age. We speculate that the antibody activities detected in the normal individuals carry out a physiologic regulatory role, as opposed to a destructive autoimmune dysfunction, because these molecules can be present in high levels throughout life.

Section: Introductionmentioning

confidence: 99%

Natural Human Antibodies to Synthetic Peptide Autoantigens: Correlations with Age and Autoimmune Disease

Marchalonis

Schluter²,

Wilson³

et al. 1993

“…Since the first description of the presence of band 3-related proteins in nucleated cells [41], proteins of the AE family have been found in all cells examined so far [3], In neu ronal cells, AE proteins seem to have the same functions as AE1 in erythrocytes, such as an ion transport, ankyrin binding, and SCA gen eration [42], Differentiation in vitro results in increased AE1 and SCA expression at the cell surface [43]. Various AE proteins (AE1, AE2 and AEO, an AE protein with structural ele ments of AE1 and AE2 [33]) are expressed in human neurons, and the neuronal expression of at least one of these proteins increases with age [33,44], Immunoabsorption studies indi cate that SCA is generated on brain AE1, and SCA-antibodies label fibrillary structures in sections from old, but not from young brains [11].…”

Section: Resultsmentioning

confidence: 99%

Involvement of Neuronal Anion Exchange Proteins in Cell Death in Alzheimer's Disease

Bosman¹,

Renkawek

Workum

et al. 1997

Anion exchange (AE) proteins are present in human neurons in the brain. Immunohistochemical data indicate that their apparent expression level increases with age, and especially with degeneration in Alzheimer’s disease-affected brain areas. The increase in immunoreactivity is probably caused by changes in AE structure that lead to an increased accessibility of hitherto hidden epitopes. These epitopes correspond to regions in the membrane domain that are involved in generation of senescent cell-specific antigen from AE1 in aging erythrocytes. Elucidation of the molecular nature of these changes and the underlying mechanisms, will lead to insight in the processes that govern aging- and degeneration-associated perturbation of membrane integrity. AE-mediated chloride/bicarbonate exchange is a major component in the regulation of intracellular pH. The functional consequences of changes in AE structure may range from acidosis, disturbance of cytoskel-eton integrity, and untimely or impaired recognition of cells by components of the immune system, such as microglia. A molecular and physiological description of these changes will establish AE proteins as valuable tools in elucidating the processes of normal aging, and the disturbances in aging-related diseases such as Alzheimer’s disease.

“…with self tissues and cells was known, this was the first unequivocal demonstration of a role for physiologic autoantibodies [51][52][53], A physiologic role for other autoantibodies has not been demonstrated [for a detailed discus sion of physiologic autoantibodies, see refs 30, 33,55,59,61,64], Since then, autoantibodies to band 3/SCA have been demonstrated to be involved in the removal of erythrocytes in a number of clini cal hemolytic anemias, sickle cell anemia, and the removal of malaria-infected erythrocytes [36,42,47,[66][67][68], In addition to their role in homeostasis, maintaining physiologic processes [1,2,[4][5][6]37], antibodies to SCA increase in systemic lupus erythematosus and rheumatoid arthritis [69]. Autoantibodies that bind to RBC in the autoimmune hemo lytic anemia of New Zealand black (NZB) mice are directed against band 3 [70,71 ].…”

Section: Introduction Travelingmentioning

confidence: 99%

“…data;16], and (d) monoclonal and polyclonal antibodies against both purified erythroid band 3 protein and its peptides react with band 3 proteins from oth er species and tissues [1-6. 28-39], Band 3 performs the same structural and functional activities in adult brain as it does in erythro cytes [1.2.4-6], It ages as cells and tissues age [2,4,5,[37][38][39][40][41][42][43][44][45][46][47][48][49]. An aging antigen, senescent cell antigen (SCA), is generated by oxidation and the breakdown of band 3 [29.…”

Section: Introduction Travelingmentioning

confidence: 99%

Brain and Erythrocyte Anion Transporter Protein, Band 3, as a Marker for Alzheimer’s Disease: Structural Changes Detected by Electron Microscopy, Phosphorylation, and Antibodies

Kay

Goodman²

1997

Band 3, a ubiquitous membrane transport, regulatory, and structural protein, is represented in brain by at least 4 isoforms. Bands 3 in brain performs the same functions as it does in erythrocytes (RBC). It is susceptible to oxidative damage, which, ultimately, terminates its life and that of the cell. We examined the changes band 3 undergoes in Alzheimer’s disease (AD) because our previous studies suggest that band 3 is a pivotal protein in neurological disease. Because we hypothesize that AD is a total body disease, we examined peripheral blood cells as well as brain tissue to determine whether the same changes occur in both. Our results indicate that posttranslational changes occur in RBC band 3 that parallel changes in brain band 3. These include decreased ³²P-phosphate labeling in vitro of band 3 polypeptides in brain and RBC, increased degradation of band 3, alterations in band 3 recognized by polyclonal and monoclonal antibodies, and decreased anion and glucose transport by blood cells. Serum autoantibodies to band 3 peptides 588-602 and 822-839 were increased in AD patients compared to controls. These band 3 residues lie in anion transport/binding regions. This is consistent with alteration of this region in AD since it is recognized as antigenically different by the patients’ immune system. Our data support an immunological component to AD. The finding that changes in RBC in AD reflect those in brain and can be recognized by antibodies should facilitate development of blood tests for diagnosis and monitoring, and early therapy. It is anticipated that identification of molecular sites of posttranslational modification of band 3 will enable us to design specific preventive and treatment strategies, and target drugs to crucial molecular sites.