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The egghead gene is required for compartmentalization in Drosophila optic lobe development.

The correct targeting of photoreceptor neurons (R-cells) in the developing Drosophila visual system requires multiple guidance systems in the eye-brain complex as well as the precise organization of the target area. Here, we report that the egghead (egh) gene, encoding a glycosyltransferase, is required for a compartment boundary between lamina glia and lobula cortex, which is necessary for appropriate R1-R6 innervation of the lamina. In the absence of egh, R1-R6 axons form a disorganized lamina plexus and some R1-R6 axons project abnormally to the medulla instead of the lamina. Mosaic analysis demonstrates that this is not due to a loss of egh function in the eye or in the neurons and glia of the lamina. Rather, as indicated by clonal analysis and cell-specific genetic rescue experiments, egh is required in cells of the lobula complex primordium which transiently abuts the lamina and medulla in the developing larval brain. In the absence of egh, perturbation of sheath-like glial processes occurs at the boundary region delimiting lamina glia and lobula cortex, and inappropriate invasion of lobula cortex cells across this boundary region disrupts the pattern of lamina glia resulting in inappropriate R1-R6 innervation. This finding underscores the importance of the lamina/lobula compartment boundary in R1-R6 axon targeting.

Animals↗

The argos gene encodes a diffusible factor that regulates cell fate decisions in the Drosophila eye.

The argos gene encodes a protein that is required for viability and that regulates the determination of cells in the Drosophila eye. A developmental analysis of argos mutant eyes indicates that the mystery cells, which are usually nonneuronal, are transformed into extra photoreceptors, and that supernumerary cone cells and pigment cells are also recruited. Clonal analysis indicates that argos acts nonautonomously and can diffuse over the range of several cell diameters. Conceptual translation of the argos gene suggests that it encodes a secreted protein.

Amino Acid Sequence↗

New targets for therapy in prostate cancer: differential display code 3 (DD3(PCA3)), a highly prostate cancer-specific gene.

Identification of new markers for diagnosis and new targets for therapy would represent a considerable advance in the treatment of prostate cancer. Differential display code 3 (DD3(PCA3)) is a novel gene with characteristics that indicate its potentially valuable role in early identification of malignancy and in the construction of interventions directed specifically toward malignantly transformed cells. DD3(PCA3) has a messenger RNA product that is highly overexpressed in tumors. Compared with other genetic markers that are associated with prostate tissue, DD3(PCA3) is the most specific marker for malignant disease. Indeed, it is not expressed in any other normal human tissue, including breast, bladder, testis, gastrointestinal organ, and musculoskeletal tissue. This specific relation of DD3(PCA3) to prostate tissue has been confirmed by reverse transcription-polymerase chain reaction analysis. Clonal investigation of the DD3(PCA3) transcription unit indicates that the gene has 4 distinct exons, which can give rise to a number of differently sized transcripts. Open reading frame analysis has also confirmed that the DD3(PCA3) exons are populated by an unusual number of stop codons. The dramatic prostate-specific expression and pronounced upregulation of DD3(PCA3) in prostate cancer suggest a unique transcriptional regulation. A quantitative assay for DD3(PCA3) would be a potentially valuable tool for the detection of malignant cells in blood, urine, or other clinical specimens, and it could have important implications for the earlier diagnosis and molecular staging of prostate cancer. Although further studies are needed, gene therapies based on identification to delineate the range of transcription factors that interact with the DD3(PCA3) promoter represent a promising area for preclinical investigation.

Adenocarcinoma↗

Clinically nonfunctioning pituitary tumors are monoclonal in origin.

Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.

Adenoma↗

Cross-reactive recognition of mouse cells expressing the bm3 and bm11 mutations within H-2Kb by H-2Kb-restricted herpes simplex virus-specific cytotoxic T lymphocytes.

Cytotoxic T lymphocytes, generated in C57BL/6 mice in response to herpes simplex virus type 1 (HSV) and known to be restricted in their recognition of HSV-encoded antigen(s) in association with the class I H-2Kb gene product, were consistently found to contain a subpopulation that recognized and lysed uninfected, SV40-transformed cells that expressed the H-2Kbm3 and H-2Kbm11 mutant class I gene products on their cell surface. The mutant cell lines, designated Lgbm3SV and Kbm11SV, share a common amino acid substitution at position 77, with the bm3 mutation having an additional amino acid substitution at position 89. Cross-reactive lysis was observed only after in vivo priming with HSV, suggesting an important role for an antigen-dependent driving step in the expansion of these cross-reactive CTL. The phenotype of the cross-reactive effector population was further confirmed as a T lymphocyte by negative-selection techniques. Limiting dilution analysis of the frequency of cross-reactive CTL precursors suggested that cross-reactivity was mediated by a subpopulation of HSV-specific CTL, and this was confirmed by clonal analysis of the reactivity patterns of short-term, HSV-specific CTL clones. However, analysis of the specificity of the cross-reactive CTL population by cold-target inhibition of bulk culture-derived CTL, or by Spearman ranking analysis of limiting dilution-derived CTL, indicated that the specificity of the cross-reactive population for HSV-infected H-2b target cells and for uninfected bm3 or bm11 target cells was quite distinct. These findings suggested that the cross-reactive CTL population played little, if any, role in the HSV-specific CTL response as measured in vitro. The findings also suggested that the HSV-specific CTL clones able to mediate cross-reactive recognition of the bm3 and bm11 targets had a higher intrinsic avidity for the foreign target than for the inducing antigen.

Amino Acids↗

Evolution of total and integrated HIV-1 DNA and change in DNA sequences in patients with sustained plasma virus suppression.

Blood samples from patients with plasma HIV-1 RNA <20 copies/ml for more than 2 years were studied. Significant decreases in total and integrated HIV-1 DNA were observed during the first 15 months of suppressive therapy before the concentrations became stable. Clonal analysis of HIV-1 pol demonstrated that the proportions of resistance mutations in DNA sequences after 2 years were lower than those in baseline DNA and RNA sequences. The changes in the clonal composition of HIV-1 env populations in three patients with evidence of changes in HIV-1 pol populations indicated a shift from predominantly R5-like viruses to predominantly X4-like viruses in two patients and the persistence of predominantly X4-like viruses in the third. Our analyses indicate the reemergence of ancestral sequences from long-lived cells or the residual production of wild-type virus from anatomic sites with limited access to antiretroviral drugs and the preferential infection of cells expressing CXCR4.

Amino Acid Sequence↗

Asynchronous differentiation of clonally related spinal cord oligodendrocytes.

Oligodendrocytes are responsible for myelination in the vertebrate central nervous system, but what controls their differentiation remains unknown. To determine if clonally related rat spinal cord oligodendrocyte precursors differentiated synchronously in a complex environment, retroviral clonal analysis was combined with immunocytochemistry using antibodies which define consecutive stages in oligodendrocyte development. In embryonic spinal cord cultures, most oligodendrocyte clones contained both differentiated oligodendrocytes and their precursors, demonstrating that clonally related oligodendrocytes differentiated asynchronously. Such asynchronous differentiation did not simply reflect differences in proliferation between clonally related cells. In young cultures, most clones were composed entirely of dividing cells. In older cultures, most clones contained nonproliferating immature precursor cells, suggesting that oligodendrocyte proliferation and differentiation are independently regulated, and differentiation is primarily regulated by environmental factors.

Animals↗

Spinal cord oligodendrocytes develop from a limited number of migratory highly proliferative precursors.

Oligodendrocytes are responsible for myelin formation in spinal cord white matter. In the mature spinal cord, the majority of white matter is localized peripherally. During early development, however, the first oligodendrocyte precursors arise in the ventral ventricular zone of the developing cord. Thus, prior to myelination, both migration and proliferation of oligodendrocyte precursors must occur. When and where these events occur is currently unclear. In the chick spinal cord, oligodendrocyte precursors express antigens recognized by the monoclonal antibody O4. Here we show that all chick spinal cord oligodendrocytes are derived from O4+ cells and all O4+ cells appear to give rise to oligodendrocytes. Analysis of the number and distribution of oligodendrocyte precursors in chick spinal cord at different stages of development suggests that relatively few cells migrate from the ventricular source which then proliferate extensively in white matter. This migration is guided by general dispersive cues. Clonal analysis of oligodendrocyte development in cultures derived from different regions of the rodent spinal cord indicated that the cells that initially populate dorsal and peripheral spinal cord retained similar clonal properties to those in ventral spinal cord, suggesting the migrating cells were immature, highly proliferative precursors. Consistent with these results, BrdU incorporation studies indicate that glial proliferation is extensive and persistent in postnatal rat spinal cord white matter. Together, these studies suggest that spinal cord white matter is initially populated by very immature precursors that then undergo extensive local proliferation prior to myelination.

Animals↗

The role of common gamma chain in human monocytes in vivo; evaluation from the studies of X-linked severe combined immunodeficiency (X-SCID) carriers and X-SCID patients who underwent cord blood stem cell transplantation.

Expression of common gamma chain (gammac) on monocytes was studied in five carriers of X-linked severe combined immunodeficiency (X-SCID) and two X-SCID patients who underwent cord blood stem cell transplantation (CBSCT). Flow cytometric analysis revealed that both gammac-negative and positive monocytes co-existed in X-SCID carriers, whereas no gammac-negative T, B or NK cells were observed in them. Clonal analysis and reverse transcription polymerase chain reaction studies revealed that 13.2-45.0% of monocytes from these carriers expressed the mutant gammac message. X-SCID patients who received CBSCT persistently possessed the majority of gammac-negative monocytes with a good clinical course. These results, together, may indicate that gammac is not essential for monocyte development/function in vivo.

Female↗

A novel surface antigen expressed by a subset of human CD3- CD16+ natural killer cells. Role in cell activation and regulation of cytolytic function.

The GL183 mAb was obtained by immunizing BALB/c mice with the E57 clone (CD7+CD2+CD3-CD16+CD56+) derived from human peripheral blood NK cells. In human peripheral blood, GL183-reactive cells ranged between 2 and 12% (mean 6.5%) in 10 different donors. Double fluorescence and FACS analysis showed that GL183+ cells were consistently included in the CD56+ or CD16+ cell populations. Moreover, since only a fraction of CD56+ or CD16+ cells (approximately 40%) coexpressed GL183 surface antigen, reactivity with GL183 mAb appears to define two subsets within the CD3- lymphocyte population expressing NK cell markers. Although, the majority of GL183+ cells were CD3-, approximately 1% expressed CD3 surface antigens. As shown by clonal analysis, these infrequent CD3+GL183+ cells coexpressed CD56 and CD16 antigens. Cloning of CD3-GL183+ or CD3-GL183- cell populations under limiting dilution conditions yielded clonal progenies that maintained their original surface phenotype. Therefore, expression or lack of expression of GL183 surface antigens represents a stable phenotypic property of a subset of human CD3- NK cells. Immunoprecipitation experiments and two-dimensional PAGE analysis indicated that GL183-reactive molecules were represented in different clones either by a single 58-kD chain or, more frequently, by two chains of approximately 55 and approximately 58 kD, respectively. Analysis of GL183+ or GL183- NK clones for their ability to lyse human (IGROV I) or murine (P815) tumor target cells indicated that GL183- clones were, on average, fivefold more efficient in inducing target cell lysis. GL183+ and GL183- clones produced comparable levels of TNF-alpha in response to PHA plus PMA or anti-CD16 mAb plus PMA. Importantly, production of TNF-alpha was also induced by stimulation of GL183+ clones with GL183 mAb plus PMA. These data indicated that GL183 antigen could mediate cell triggering. This concept was confirmed by the analysis of Ca2+ mobilization, as GL183 mAb induced (in GL183+ clones) increments of [Ca2+]i comparable with those induced by PHA. Moreover, GL183 mAb, or its F(ab')2 fragments, strongly enhanced the cytolytic activity of GL183+ clones against a panel of human tumor target cells, including U937, Raji, IGROV I, M14, and A549. In contrast, GL183 mAb, but not the F(ab')2 fragments, sharply inhibited the cytolytic activity of the same clones against P815, M12, and P3U1 murine target cells. In this case, the effect of GL183 mAb (inhibition) was opposite that of PHA or of stimulatory anti-CD2 or anti-CD16 mAbs, which consistently enhanced the target cell lysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Differential myogenicity of satellite cells isolated from extensor digitorum longus (EDL) and soleus rat muscles revealed in vitro.

Following muscle damage, fast- and slow-contracting fibers regenerate, owing to the activation of their satellite cells. In rats, crush-induced regeneration of extensor digitorum longus (EDL, a fast muscle) and soleus (a slow muscle) present different characteristics, suggesting that intrinsic differences exist among their satellite cells. An in vitro comparative study of the proliferation and differentiation capacities of satellite cells isolated from these muscles is presented there. We observed several differences between soleus and EDL satellite cell cultures plated at high density on gelatin-coated dishes. Soleus satellite cells proliferated more actively and fused into myotubes less efficiently than EDL cells. The rate of muscular creatine kinase enzyme appeared slightly lower in soleus than in EDL cultures at day 11 after plating, when many myotubes were formed, although the levels of muscular creatine kinase mRNA were similar in both cultures. In addition, soleus cultures expressed higher levels of MyoD and myogenin mRNA and of MyoD protein than EDL satellite cell cultures at day 12. A clonal analysis was also carried out on both cell populations in order to determine if distinct lineage features could be detected among satellite cells derived from EDL and soleus muscles. When plated on gelatin at clonal density, cells from both muscles yielded clones within 2 weeks, which stemmed from 3-15 mitotic cycles and were classified into three classes according to their sizes. Myotubes resulting from spontaneous fusion of cells from the progeny of one single cell were seen regardless of the clone size in the standard culture medium we used. The proportion of clones showing myotubes in each class depended on the muscle origin of the cells and was greater in EDL- than in soleus-cell cultures. In addition, soleus cells were shown to improve their differentiation capacity upon changes in the culture condition. Indeed, the proportions of clones showing myotubes, or of cells fusing into myotubes in clones, were increased by treatments with a myotube-conditioned medium, with phorbol ester, and by growth on extra-cellular matrix components (Matrigel). These results, showing differences among satellite cells from fast and slow muscles, might be of importance to muscle repair after trauma and in pathological situations.

Animals↗

Activation of preexisting T cell clones by targeted interleukin 2 therapy.

The induction of an immunological antitumor response capable of eradicating metastatic tumors is the ultimate goal of immunotherapy. We have recently shown that this can be achieved by interleukin 2 (IL-2) therapy directed to the tumor microenvironment by a recombinant antibody-IL-2 fusion protein. It is not known, however, whether this curative treatment is associated with a predominance of T cells carrying specific T cell receptor variable beta regions (TCRBV) or the presence of clonally expanded T cells. To address this question, we have used a quantitative reverse transcriptase-coupled PCR method to analyze the TCRBV region repertoire in tumor-infiltrating lymphocytes of treated and untreated animals. As controls the TCRBV region repertoire was analyzed in blood and skin from disease-free animals. The results indicate an overexpression of TCRBV5 in the tumors of all treated mice and an additional overexpression of individual regions in each tumor. Direct sequencing of these TCRBV regions did not reveal any evidence of clonal expansions. However, since clonal expansions could exist as subpopulations in highly expressed regions, not detectable by direct sequencing, a denaturing gradient gel electrophoresis assay was used for clonal analysis of TCRBV PCR products. Denaturing gradient gel electrophoresis analysis of selected TCRBV regions revealed the presence of clonotypic T cells in tumors from both treated and untreated animals. These data indicate that targeted IL-2 therapy in this model does not induce clonal T cell responses de novo, rather it acts as an activator for an already existing population of clonotypic T cells.

Animals↗

Developmental genetics of the 2C-D region of the Drosophila X chromosome.

We have conducted a genetic and developmental analysis of genes within the 2C-D area of the X chromosome. Phenotypes of 33 mutations representing nine adjacent complementation groups including eight recessive lethals and one visible homeotic mutation (polyhomeotic) are described. Germline clonal analysis of the eight zygotic lethals has revealed three types of gene requirements: normal activity at two pupal lethal loci (corkscrew and C204) and one larval lethal locus (ultraspiracle) is required for normal embryogenesis; normal activity at three larval lethal loci (DF967, VE651 and Pgd) is required for normal oogenesis; and activity at only one locus (EA82), a larval lethal, appears to have no maternal requirement. Ambiguous results were obtained for the GF316 lethal complementation group. Analysis of mitotic figures of the pupal lethals indicates that C204 disrupts an essential mitotic function. This result correlates with the preblastoderm arrest observed among embryos derived from germline clones of C204. Embryos derived from germline clones of corkscrew (csw) exhibit a "twisted" phenotype. The recessive lethal ultraspiracle (usp) disrupts the organization of the posterior tip of the larval both zygotically and maternally: second instar usp/Y larvae derived from heterozygous usp/+ mothers possess an extra set of spiracles, whereas usp/Y embryos derived from females possessing a germline clone (usp/usp) exhibit a localized ventral defect in the ninth or posterior eighth abdominal segment. Analysis of the phenotypes of deficiency-hemizygous embryos indicates the presence of an embryonic zygotic lethal locus, as yet unidentified, which produces central nervous system and ventral hypoderm degeneration. Additional information on the genetic organization of loci within the adjacent 2E area are also described.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Analysis with antiidiotype antibody of a patient with chronic lymphocytic leukemia and a large cell lymphoma (Richter's syndrome).

A murine monoclonal antibody made against an idiotypic determinant (Id) of surface IgM/IgD lambda molecules on chronic lymphocytic leukemia (CLL) cells of a 71-year-old woman was used for clonal analysis by two-color immunofluorescence. The anti-Id antibody identified IgM+/IgD+/lambda+ B cells as the predominant cell type of her CLL clone. In addition, substantial proportions of the IgG and IgA B cells and most of the IgM plasma cells in her bone marrow and blood were Id+. Six years after diagnosis, the patient died of respiratory failure due to infiltration of lungs by malignant cells. Autopsy revealed a dramatic change in the tumor cell morphology. The lungs, hilar nodes, and liver were infiltrated by a diffuse large cell lymphoma admixed with the leukemic cells. By immunohistologic staining these anaplastic lymphoma cells were IgM+/IgD-/lambda+ B cells expressing the same Id noted earlier on the CLL cells. The immunoglobulin gene rearrangement pattern on Southern blot analysis was also the same in leukemic blood cells and in the tissues involved by the lymphoma. Thus, the combination of antiidiotype and immunoglobulin gene analyses in this patient with Richter's syndrome revealed that a CLL clone, seemingly "frozen" in differentiation, was actually undergoing isotype switching, differentiation into plasma cells, and evolution into a rapidly growing and fetal lymphoma.

Aged↗

Is the 15-in situ clone protocol necessary to detect amniotic fluid mosaicism?

OBJECTIVE: Our purpose was to evaluate the 15-clone analysis for detecting amniotic fluid mosaicism by the in situ method. STUDY DESIGN: A 10-year review was performed of all amniotic fluid mosaicism cases at two institutions using the in situ method exclusively, with sequential clonal analysis to determine the first and second clone in which the abnormal cell line occurred. RESULTS: Of the 28,497 amniotic fluid samples, 73 met criteria for amniotic fluid mosaicism by in situ method (0.26%). There were 54 cases (0.19%) with potential clinical significance (23 autosome and 31 sex chromosome mosaicism); 49 of the 54 cases (89%) were detected in the first six clones, including 22 of 23 involving autosomes and 27 of 31 involving sex chromosomes. In one of the six cases detected after clone 6 (46,XX/47,XX,+21) the mosaic cell line was present in 20% of the clones analyzed and was followed by a voluntary termination of the pregnancy. In the other five cases amniotic fluid mosaicism was present in < 20% of the clones; these included one case of 46,XX/47,XX+mar (15% amniotic fluid mosaicism, voluntary termination of pregnancy), two cases of 45,X/46,XY (10% to 12% amniotic fluid mosaicism, both normal at birth), and two cases of 45,X/46,XX (8% amniotic fluid mosaicism, lost to follow-up; 12% amniotic fluid mosaicism, voluntary termination of pregnancy). By limiting the analysis to six clones, approximately 20% of analysis time could be saved per case, but one autosomal amniotic fluid mosaicism case per 10,000 samples could potentially be missed. CONCLUSION: Reducing the number of clones analyzed by in situ method could result in increased efficiency, decreased costs, and minimal loss of sensitivity.

Amniotic Fluid↗

Clinical significance of clonality in thyroid nodules.

BACKGROUND: Many different neoplastic and hyperplastic thyroid diseases present with clinically apparent thyroid nodules. Clonality analysis indicates whether a nodule arises from the polyclonal proliferation of a group of cells or forms a clone from a genetically altered cell and thus provides objective information on the origin of the thyroid nodules. Clonality was studied in thyroid nodules using the polymerase chain reaction (PCR) assay in the X-linked human androgen receptor (HUMARA) gene by random X chromosome inactivation in women. METHODS: DNA samples were obtained from 28 nodules in 21 women. All nodules and non-tumour thyroid tissues were fractioned selectively under a cryostat. Genomic DNA was isolated and digested with HhaI. PCR amplification of the HUMARA locus was performed using PCR mixtures containing [alpha-32P]2'-deoxycytidine 5'-triphosphate. The PCR products were analysed by denaturing gel electrophoresis. RESULTS: The HUMARA alleles were heterogeneous in 18 of 21 patients. Among the 23 nodules from 18 patients, all of the eight papillary thyroid carcinomas were monoclonal. Two solitary nodules from follicular adenomas were monoclonal. Of the 13 follicular nodules from nodular goitres, ten were polyclonal and three were monoclonal. The monoclonal follicular nodules were larger in size (3.5 versus 2.0 cm, P< 0.05) and had a tendency towards more cystic changes than polyclonal nodules. CONCLUSION: PCR-based clonality study of thyroid nodules may help to distinguish hyperplastic from neoplastic nodules.

Adenoma↗

Induction of antigen-reactive and IL-2 receptor bearing cells following oral immunization in humans.

A human model of oral immunization using two forms of HI antigen preparation was studied. Oral immunization with killed HI (monobacterial) or HI in a polybacterial mix (polybacterial) induced an enhanced antigen-driven proliferative response in circulating PBL of normal subjects as well as an increase in the precursor frequency of HI antigen-specific cells using limiting dilution analysis. However, the proliferative response was better maintained at a high level in subjects after completion of immunization with the polybacterial vaccine, whereas the response was small and transient following oral immunization with the monobacterial vaccine. Clonal analysis of the proliferative response demonstrated that the precursor frequency of HI antigen-specific cells in the circulating pool was not expanded to account for the differences, despite repeated ingestion of the vaccine. An analysis of PBL following oral immunization using anti-TAC monoclonal antibody revealed an increase in the number of IL-2 receptor-bearing cells in subjects orally immunized with the polybacterial vaccine, with maximal numbers occurring at day 62 when the number of precursors fell but the proliferative response remained high. This suggests that the enhanced and sustained proliferation in bulk cultures is due in part to a contribution to the overall proliferation by in vivo polyclonally-activated IL-2 receptor positive cells which proliferate in the presence of IL-2. Taken together, the results obtained are consistent with the concept that 'restricted' cell activation may be important in the mechanism of selective protection found following oral immunization with monobacterial HI vaccine.

Administration, Oral↗

Immunoglobulin gene analysis in polyneuropathy associated with IgM monoclonal gammopathy.

Antineural antibody activity is the implicated pathogenic mechanism in polyneuropathy associated with monoclonal gammopathy. Recognition of antigen depends on immunoglobulin variable regions, encoded by V genes. We studied V(H)DJ(H) and V(L)J(L) gene use in monoclonal B cells by clonal analysis in 20 patients with polyneuropathy and IgM monoclonal gammopathy. V genes associated with bacterial responses appear over-represented and V(H)3-23 was preferentially used, without association with specific D, J(H) or V(L)J(L). V genes revealed somatic mutation and intraclonal variation was found in 9 of 20 patients. Polyneuropathy associated with monoclonal gammopathy may be caused by an immune response to bacterial antigens, which recruit somatically mutated autoreactive B cells.

Aged↗