LOC102723407 - putative V-set and immunoglobulin domain-containing-like protein IGHV4OR15-8
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Publication
Journal: Molecular Medicine
May/11/2009
Abstract
Chronic lymphocytic leukemia (CLL) represents the outgrowth of a CD5(+) B cell. Its etiology is unknown. The structure of membrane Ig on CLL cells of unrelated patients can be remarkably similar. Therefore, antigen binding and stimulation could contribute to clonal selection and expansion as well as disease promotion. Initial studies suggest that CLL mAbs bind autoantigens. Since apoptosis can make autoantigens accessible for recognition by antibodies, and also create neo-epitopes by chemical modifications occurring naturally during this process, we sought to determine if CLL mAbs recognize autoantigens associated with apoptosis. In general, ~60% of CLL mAbs bound the surfaces of apoptotic cells, were polyreactive, and expressed unmutated IGHV. mAbs recognized two types of antigens: native molecules located within healthy cells, which relocated to the external cell surface during apoptosis; and/or neoantigens, generated by oxidation during the apoptotic process. Some of the latter epitopes are similar to those on bacteria and other microbes. Although most of the reactive mAbs were not mutated, the use of unmutated IGHV did not bestow autoreactivity automatically, since several such mAbs were not reactive. Particular IGHV and IGHV/D/J rearrangements contributed to autoantigen binding, although the presence and degree of reactivity varied based on specific structural elements. Thus, clonal expansion in CLL may be stimulated by autoantigens occurring naturally during apoptosis. These data suggest that CLL may derive from normal B cells whose function is to remove cellular debris, and also to provide a first line of defense against pathogens.
Publication
Journal: Journal of Molecular Biology
March/17/1999
Abstract
In the bone marrow, diversity in the primary antibody repertoire is created by the combinatorial rearrangement of different gene segments and by the association of different heavy and light chains. During the secondary response in the germinal centres, antibodies are diversified by somatic mutation and possibly by further rearrangements, or "receptor editing". Here, we have analysed the pairings of heavy and light chain variable domains (VH and VL) in 365 human IgG+ B cells from peripheral blood, and established that these pairings are largely random. The repertoire is dominated by a limited number of pairings of segments and folds. Among these pairings we identified two identical mutated heavy chains in combination with two different mutated light chains (one kappa and one lambda). This shows that receptor editing occurs in the human periphery and that the same antibody lineage can be subjected to both receptor editing and somatic hypermutation. This suggests that receptor editing may be used together with somatic mutation for the affinity maturation of antibodies. We also propose that receptor editing has shaped variable gene segment use and the evolution of V gene families.
Publication
Journal: Nature Communications
June/5/2017
Abstract
Comprehensive knowledge of immunoglobulin genetics is required to advance our understanding of B cell biology. Validated immunoglobulin variable (V) gene databases are close to completion only for human and mouse. We present a novel computational approach, IgDiscover, that identifies germline V genes from expressed repertoires to a specificity of 100%. IgDiscover uses a cluster identification process to produce candidate sequences that, once filtered, results in individualized germline V gene databases. IgDiscover was tested in multiple species, validated by genomic cloning and cross library comparisons and produces comprehensive gene databases even where limited genomic sequence is available. IgDiscover analysis of the allelic content of the Indian and Chinese-origin rhesus macaques reveals high levels of immunoglobulin gene diversity in this species. Further, we describe a novel human IGHV3-21 allele and confirm significant gene differences between Balb/c and C57BL6 mouse strains, demonstrating the power of IgDiscover as a germline V gene discovery tool.
Publication
Journal: Journal of Immunology
June/20/2000
Abstract
The VH4 genes expressed by both resting and in vivo-activated subepithelial (SE) B cells from human tonsils were studied. Resting SE B cells were subdivided according to the presence (IgDlow) or absence (IgM-only) of surface IgD. CD27 was abundant on activated SE B cells and low on resting IgM-only B cells. Resting IgDlow SE B cells could be subdivided into CD27low and CD27high cell fractions. Resting IgDlow SE B cells displayed VH4 genes with a substantial number of mutations (13/29 of the molecular clones were mutated), whereas 25/26 of the clones from resting IgM-only SE B cells were unmutated. Moreover, mutated VH4 genes were detected mainly within the CD27high cell fraction of the IgDlow SE B cells. Several identical unmutated VH4DJH sequences (11/32) were found in different molecular clones from resting IgM-only SE B cells, suggesting local cellular expansion. Both unmutated (14/25) and mutated (11/25) sequences were found in mu transcripts of activated SE B cells. Extensive mutation was observed in the gamma transcripts of activated SE B cells. Therefore, SE B cells are heterogeneous, being comprised of B cells with mutated Ig VH4 genes, that are Ag-experienced B cells, and a subset of B cells with unmutated VH4 genes that are either virgin cells or cells driven by Ags that did not induce or select for V gene mutations.
Publication
Journal: Clinical Immunology
November/22/1999
Abstract
Immune responses change in aging humans, but it is not known whether there is an age-associated change in the expressed B cell repertoire. We compared Ig VH cDNA libraries from circulating B cells of five elderly and three young human adults. As in young persons, nearly two-thirds of the cDNA clones from older subjects had zero to three V(H) mutations, although there was more individual variation among the elderly. V(H)4 family expression increased in older subjects, both in unmutated and in mutated cDNA clones, whereas V(H)3 family expression predominated in young adults. To test for bias toward activated cells in the cDNA libraries, we studied two older persons by both cDNA library analysis and single-cell RT-PCR. In one subject, more than 85% of VH segments were unmutated by either analysis. In the second, mutated Ig segments were much more frequent in cDNA clones than in consecutive single cells; however, V(H) family usage and high representation of particular genes were similar in both analyses. While aging humans continue to produce naive B cells with unmutated Ig genes, a shift to greater use of the V(H)4 family members and expression of particular genes may reflect changes in selection of developing B cells before affinity maturation toward reactivity with foreign antigen.
Publication
Journal: Blood
December/14/2005
Abstract
Immunoglobulin kappa (IGK) and immunoglobulin lambda (IGL) light chain repertoire was analyzed in 276 chronic lymphocytic leukemia (CLL) cases and compared with the relevant repertoires from normal, autoreactive, and neoplastic cells. Twenty-one functional IGKV genes were used in IGKV-J rearrangements of 179 kappa-CLL cases; the most frequent genes were IGKV3-20(A27), IGKV1-39/1D-39(O2/O12), IGKV1-5(L12), IGKV4-1(B3), and IGKV2-30(A17); 90 (50.3%) of 179 IGK sequences were mutated (similarity < 98%). Twenty functional IGLV genes were used in IGLV-J rearrangements of 97 lambda-CLL cases; the most frequent genes were IGLV3-21(VL2-14), IGLV2-8(VL1-2), and IGLV2-14(VL1-4); 44 of 97 IGL sequences (45.4%) were mutated. Subsets with "CLL-biased" homologous complementarity-determining region 3 (CDR3) were identified: (1) IGKV2-30-IGKJ2, 7 sequences with homologous kappa CDR3 (KCDR3), 5 of 7 associated with homologous IGHV4-34 heavy chains; (2) IGKV1-39/1D-39-IGKJ1/4, 4 unmutated sequences with homologous KCDR3, 2 of 4 associated with homologous IGHV4-39 heavy chains; (3) IGKV1-5-IGKJ1/3, 4 sequences with homologous KCDR3, 2 of 4 associated with unmutated nonhomologous IGHV4-39 heavy chains; (4) IGLV1-44-IGLJ2/3, 2 sequences with homologous lambda CDR3 (LCDR3), associated with homologous IGHV4-b heavy chains; and (5) IGLV3-21-IGLJ2/3, 9 sequences with homologous LCDR3, 3 of 9 associated with homologous IGHV3-21 heavy chains. The existence of subsets that comprise given IGKV-J/IGLV-J domains associated with IGHV-D-J domains that display homologous CDR3 provides further evidence for the role of antigen in CLL pathogenesis.
Publication
Journal: Immunity
September/17/2018
Abstract
Respiratory syncytial virus (RSV) is a leading cause of infant mortality, and there are currently no licensed vaccines to protect this vulnerable population. A comprehensive understanding of infant antibody responses to natural RSV infection would facilitate vaccine development. Here, we isolated more than 450 RSV fusion glycoprotein (F)-specific antibodies from 7 RSV-infected infants and found that half of the antibodies recognized only two antigenic sites. Antibodies targeting both sites showed convergent sequence features, and structural studies revealed the molecular basis for their recognition of RSV F. A subset of antibodies targeting one of these sites displayed potent neutralizing activity despite lacking somatic mutations, and similar antibodies were detected in RSV-naive B cell repertoires, suggesting that expansion of these B cells in infants may be possible with suitably designed vaccine antigens. Collectively, our results provide fundamental insights into infant antibody responses and a framework for the rational design of age-specific RSV vaccines.
Publication
Journal: European Journal of Immunology
February/7/1993
Abstract
The repertoire of immunoglobulin expressed very early in human development was approached by cloning and sequencing 55 rearranged and 11 germ-line VH transcripts, after amplification by polymerase chain reaction of cDNA libraries derived from two fetal livers at 8 and 13 weeks of gestation. All families with the exception of VH2, were expressed as soon as 8 weeks, with preferential usage of certain germ-line genes. Very few somatic mutations, randomly localized, were identified. By contrast, in a series of clones derived from the same VDJ rearrangement using the VH6 family, extensive mutations had taken place, mostly accumulated in the third complementarity-determining region (CDR3) suggesting that the specialized enzymatic machinery was at hand very early during human development. Some other characteristics of the fetal repertoire also emerged, namely increased usage of JH3 and JH2, as compared to the adult pattern, where JH4 is dominant and reduced length of the D/CDR3 regions. All D gene families were identified, and their usage frequently involved D-D fusions. N diversity was present very early, and increased with age. Identification of germ-line transcripts pertaining to all six VH families including pseudogenes, in the E55 library, revealed a population very different as compared to rearranged gene transcripts. This suggests that a large portion of VH locus is accessible for transcription, bringing no evidence of correlation between preferential rearrangement of a given VH gene and its localization in the locus.
Publication
Journal: Journal of Immunology
February/21/2007
Abstract
During the perinatal period the development of the IgH chain CDR3 (CDR-H3) repertoire of IgM transcripts is maturity-dependent and not influenced by premature exposure to Ag. To study whether maturity-dependent restrictions also predominate in the perinatal IgG repertoire we compared 1000 IgG transcripts from cord blood and venous blood of extremely preterm neonates (24-28 wk of gestation) and of term neonates from birth until early infancy with those of adults. We found the following. First, premature contact with the extrauterine environment induced the premature development of an IgG repertoire. However after preterm birth the diversification of the IgG repertoire was slower than that after term birth. Second, the IgG repertoire of preterm neonates retained immature characteristics such as short CDR-H3 regions and overrepresentation of D(H)7-27. Third, despite premature exposure to the extrauterine environment, somatic mutation frequency in IgG transcripts of preterm infants remained low until they reached a postconceptional age corresponding to the end of term gestation. Thereafter, somatic mutations accumulated with age at similar rates in preterm and term neonates and reached 30% of the adult level after 6 mo. In conclusion, class switch was inducible already at the beginning of the third trimester of gestation, but the developing IgG repertoire was characterized by similar restrictions as those of the developing IgM repertoire. Those B cells expressing more "mature" H chain sequences were not preferentially selected into the IgG repertoire. Therefore, the postnatal IgG repertoire of preterm infants until the expected date of delivery differs from the postnatal repertoire of term neonates.
Publication
Journal: Blood
December/13/2004
Abstract
Several characteristics of the immunoglobulin (Ig) repertoire in fetuses and adults set them apart from each other. Functionally, this translates into differences in the affinity and effectiveness of the humoral immune response between adults and the very young. At least 2 possibilities could explain these differences: (1) fetal and adult lymphocyte progenitors differ significantly in their potential to form a diverse repertoire, and (2) factors extrinsic to the immunoglobulin locus are more influential to the character of the repertoire. To address this we used nonobese diabetic-severe combined immunodeficient-beta(2) microglobulin knockout (NOD/SCID/beta(2)m(-/-)) mice reconstituted with human B-cell progenitors to compare the immunoglobulin repertoire potential of human fetal, cord blood, and adult sources. We found nearly identical VH and JH gene segment use and only modest differences in the third complementarity determining region of the immunoglobulin heavy chain (HCDR3). We conclude that the repertoire potential is remarkably similar regardless of the age of the individual from which progenitors are derived. Age-related differences in the immunoglobulin repertoire and variance of B-cell responses to immunization appear to arise from selection rather than from changes in recombination of the immunoglobulin locus itself. From the standpoint of the Ig repertoire, an immune system reconstituted from fetal or neonatal stem cells would likely be as diverse as one generated from adult bone marrow.
Publication
Journal: Clinical and Experimental Allergy
May/26/2004
Abstract
BACKGROUND
IgE is the pivotal-specific effector molecule of allergic reactions yet it remains unclear whether the elevated production of IgE in atopic individuals is due to superantigen activation of B cell populations, increased antibody class switching to IgE or oligoclonal allergen-driven IgE responses.
OBJECTIVE
To increase our understanding of the mechanisms driving IgE responses in allergic disease we examined immunoglobulin variable regions of IgE heavy chain transcripts from three patients with seasonal rhinitis due to grass pollen allergy.
METHODS
Variable domain of heavy chain-epsilon constant domain 1 cDNAs were amplified from peripheral blood using a two-step semi-nested PCR, cloned and sequenced.
RESULTS
The VH gene family usage in subject A was broadly based, but there were two clusters of sequences using genes VH 3-9 and 3-11 with unusually low levels of somatic mutations, 0-3%. Subject B repeatedly used VH 1-69 and subject C repeatedly used VH 1-02, 1-46 and 5a genes. Most clones were highly mutated being only 86-95% homologous to their germline VH gene counterparts and somatic mutations were more abundant at the complementarity determining rather than framework regions. Multiple sequence alignment revealed both repeated use of particular VH genes as well as clonal relatedness among clusters of IgE transcripts.
CONCLUSIONS
In contrast to previous studies we observed no preferred VH gene common to IgE transcripts of the three subjects allergic to grass pollen. Moreover, most of the VH gene characteristics of the IgE transcripts were consistent with oligoclonal antigen-driven IgE responses.
Publication
Journal: Molecular Medicine
August/2/2012
Abstract
An infectious etiology has been proposed for many human cancers, but rarely have specific agents been identified. One difficulty has been the need to propagate cancer cells in vitro to produce the infectious agent in detectable quantity. We hypothesized that genome amplification from small numbers of cells could be adapted to circumvent this difficulty. A patient with concomitant chronic lymphocytic leukemia (CLL) and polycythemia vera (PV) requiring therapeutic phlebotomy donated a large amount of phlebotomized blood to test this possibility. Using genome amplification methods, we identified a new isolate (BIS8-17) of torque teno virus (TTV) 10. The presence of blood isolate sequence 8-17 (BIS8-17) in the original plasma was confirmed by polymerase chain reaction (PCR), validating the approach, since TTV is a known plasma virus. Subsequent PCR testing of plasmas from additional patients showed that BIS8-17 had a similar incidence (~20%) in CLL (n = 48) or PV (n = 10) compared with healthy controls (n = 52). CLL cells do not harbor BIS8-17; PCR did not detect it in CLL peripheral blood genomic deoxyribonucleic acid (DNA) (n = 20). CLL patient clinical outcome or prognostic markers (immunoglobulin heavy chain variable region [IGHV ] mutation, CD38 or zeta-chain associated protein kinase 70 kDa [ZAP-70]) did not correlate with BIS8-17 infection. Although not causative to our knowledge, this is the first reported isolation and detection of TTV in either CLL or PV. TTV could serve as a covirus with another infectious agent or TTV variant with rearranged genetic components that contribute to disease pathogenesis. These results prove that this method identifies infectious agents and provides an experimental methodology to test correlation with disease.
Publication
Journal: Molecular Medicine
June/2/2004
Abstract
Although the changes that occur in Ig V region genes during a B lymphocyte's response to antigen usually result from point mutations, nucleotide insertion and deletion also alter gene sequence. We identified nucleotide insertions and deletions (3 to 12 bp) at a frequency of 1.34%, in Ig V gene cDNA from B lymphocytes residing in the synovial tissues of patients with rheumatoid arthritis. Because the added or lost nucleotides occurred in multiples of 3, they maintained the original reading frame and coded a potentially intact receptor. These V gene modifications were generated somatically, because they were identified in the original cDNA by HCDR3-specific polymerase chain reaction and were not found in other B cells using the same VH genes. Insertions and deletions were detected only in IgG+ and IgA+ transcripts, which exhibited 3 times more point mutations than IgM+ transcripts. In addition, they were usually found in the complementarity determining region, typical targets of somatic mutation. The occurrence of insertion/ deletion in isotype-switched cDNA with higher numbers of V gene mutations that localized to hot spots for V gene mutation suggests that these diversification events were related to the somatic hypermutation process. In support of this, an AGY hot spot motif and a short stretch of DNA similar in sequence to the inserted or deleted segments could be found next to the insertions/deletions, suggesting that these modifications arose from DNA duplication following DNA stand breaks. Thus, nucleotide insertion/deletion can lead to B-cell receptor diversification in B lymphocytes that clonally expand in synovial tissues of patients with rheumatoid arthritis.
Publication
Journal: Immunology
November/4/1999
Abstract
The presence of clonally-related B-lymphocyte aggregates within synovial lining tisue of rheumatoid arthritis (RA) patients suggests a germinal centre-like reaction, which may hold implications for disease pathogenesis and the causes of chronic inflammation. We studied 250 rheumatoid factor (RF) heavy-chain sequences cloned from the synovium of three patients with RA, to determine whether they undergo both somatic mutation and isotype switching consistent with this hypothesis. Size analysis of immunoglobulin heavy-chain cDNAs from synovial RF+ B cells revealed oligoclonal RF+ populations and identically-sized VH-D-JH transcripts of different immunoglobulin isotypes. Sequencing of individual inserts selected from cloned immunoglobulin heavy-chain cDNAs demonstrated a clonal relationship between immunoglobulin M (IgM) RF and IgA RF, suggesting that this isotype switch occurred in synovium. Furthermore, most somatic mutations were found to have occurred after this isotype switch. This finding suggests that the RA synovial microenvironment sustains somatic mutation and isotype switching in RF-specific B lymphocytes akin to secondary lymphoid organs.
Publication
Journal: Journal of Clinical Investigation
April/13/2008
Abstract
Survival of patients with B cell chronic lymphocytic leukemia (B-CLL) can be predicted by analysis of mutations in the immunoglobulin heavy chain variable gene (IGHV). Patients without mutations (unmutated [UM]) are at greater risk for disease progression and death than patients with mutations (M). Despite this broad prognostic difference, there remains wide intragroup variation in the clinical outcome of UM patients, especially those with low/intermediate Rai risk disease. We evaluated UM B-CLL patients with low/intermediate Rai risk to determine the relationship between IGHV, IGH diversity (IGHD), and IGH joining (IGHJ) gene usage and time to treatment (TTT). Irrespective of IGHV usage, UM patients whose B-CLL cells expressed the IGHD3-3 gene had a significantly shorter TTT than other UM B-CLL patients, and specifically, use of the IGHD3-3 gene in reading frame 2 (RF2) predicted shorter TTT. As expected, Rai risk was the best single prognostic factor for TTT; however, IGHD usage was also a significant variable for TTT. Therefore, both IGHD gene and IGHD RF usage have prognostic relevance in UM B-CLL patients with low/intermediate Rai risk disease. In addition, these data support the concept that antigen-driven selection of specific Ig receptors plays a role in the clinical course of B-CLL.
Publication
Journal: Leukemia Research
June/9/2008
Abstract
Clinical data and immunoglobulin variable heavy chain (IgVH) gene configuration were analyzed in 47 CLL patients, exposed to ionizing radiation (IR) due to Chernobyl NPP accident, and 141 non-exposed patients. Clean-up workers of the second quarter of 1986 (n=19) were picked out as separate group with the highest number of unmutated cases (94.4%), increased usage of IgVH1-69 (33.3%) and IgVH3-21 (16.7%) genes, high frequency of secondary solid tumors (6 cases) and Richter transformation (4 cases). These preliminary data suggest that CLL in the most suffered contingent due to Chernobyl NPP accident might have some specific features.
Publication
Journal: Blood
September/11/2003
Abstract
The enhanced adhesion of sickle red blood cells (RBCs) to the vascular endothelium and subendothelial matrix likely plays a significant role in the pathogenesis of vaso-occlusion in sickle cell disease. Sickle RBCs have enhanced adhesion to the plasma and extracellular matrix protein thrombospondin-1 (TSP) under conditions of flow in vitro. In this study, we sought to develop antibodies that bind TSP from a highly diverse library of human single-chain Fv fragments (scFvs) displayed on filamentous phage. Following 3 rounds of phage selection of increasing stringency 6 unique scFvs that bound purified TSP by enzyme-linked immunosorbent assay were isolated. Using an in vitro flow adhesion assay, 3 of the 6 isolated scFvs inhibited the adhesion of sickle RBCs to immobilized TSP by more than 40% compared with control scFvs (P <.001). Furthermore, scFv TSP-A10 partially inhibited sickle RBC adhesion to activated endothelial cells (P <.005). Using TSP proteolytic fragments to map the binding site, we showed that 2 of the inhibitory scFvs bound an epitope in the calcium-binding domain or proximal cell-binding domain of TSP, providing evidence for the role of these domains in the adhesion of sickle RBCs to TSP. In summary, we have isolated a panel of scFvs that specifically bind to TSP and differentially inhibit sickle RBC adhesion to surface-bound TSP under flow conditions. These scFvs will be useful reagents for investigating the role of the calcium and cell-binding domains of TSP in sickle RBC adhesion.
Publication
Journal: JCI insight
February/19/2017
Abstract
Xenografting primary tumor cells allows modeling of the heterogeneous natures of malignant diseases and the influences of the tissue microenvironment. Here, we demonstrate that xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated autologous T cells into alymphoid mice results in considerable CLL B cell division and sizable T cell expansion. Nevertheless, most/all CD5+CD19+ cells are eventually lost, due in part to differentiation into antibody-secreting plasmablasts/plasma cells. CLL B cell differentiation is associated with isotype class switching and development of new IGHV-D-J mutations and occurs via an activation-induced deaminase-dependent pathway that upregulates IRF4 and Blimp-1 without appreciable levels of the expected Bcl-6. These processes were induced in IGHV-unmutated and IGHV-mutated clones by Th1-polarized T-bet+ T cells, not classical T follicular helper (Tfh) cells. Thus, the block in B cell maturation, defects in T cell action, and absence of antigen-receptor diversification, which are often cardinal characteristics of CLL, are not inherent but imposed by external signals and the microenvironment. Although these activities are not dominant features in human CLL, each occurs in tissue proliferation centers where the mechanisms responsible for clonal evolution operate. Thus, in this setting, CLL B cell diversification and differentiation develop by a nonclassical germinal center-like reaction that might reflect the cell of origin of this leukemia.
Publication
Journal: Terapevticheskii Arkhiv
November/2/2000
Abstract
OBJECTIVE
To compare forms of chronic lymphoid leukemia (CLL) regarding mutational status of immunoglobulin variable genes.
METHODS
We have compared clinical, prognostic and immunophenotypic data obtained on 25 cases with different mutational status of IgV genes. There were 10 patients in the mutated group (median age 49.2 years, male to female ratio = 7:3), and 15 patients in unmutated group (median age 46.5, M:F = 13:2).
RESULTS
Statistically significant differences were noted in overall survival and CD38 expression. 5-year overall survival in unmutated group was 35%, in mutated group 80% (p = 0.07). In unmutated group CD38 was expressed on more than 50% of cells in 7 out of 14 patients, while in the mutated group in 0 of 8 patients (p = 0.007). We noted high frequency of VH1-69 gene usage in unmutated group (7 of 15 patients), while in mutated group it was used in only 1 case of 10.
CONCLUSIONS
We confirm the differences between groups of CLL with different mutational status of IgV genes. Highly restricted usage of VH-genes and CD38 expression possibly suggest that unmutated group also arises from antigen driven cells.
Publication
Journal: European Journal of Immunology
November/9/1992
Abstract
A human T cell lymphoma has been described in which an inversion of chromosome 14 results in fusion of an immunoglobulin heavy chain VH with a T cell receptor J alpha segment, potentially resulting in a chimeric protein with immunoglobulin VH region recognition plus T cell receptor effector functions. Examination of the mRNA species expressed from the IgT gene in this lymphoma shows a variety of forms but all IgT mRNA include the T cell-specific exon, ET, previously located in the distal part of the VH locus. In such mRNA species, the normal leader exon of the Ig VH segment, which encodes most of the hydrophobic signal peptide, is replaced by the short ET exon encoding mainly non-hydrophobic residues. Two forms of this mRNA exist which lack the Ig VH leader sequence and thus potentially yield non-membrane proteins in the T cell lymphoma.