The Ig(kappa) enhancer influences the ratio of Ig(kappa) versus Ig(lambda) B lymphocytes.

We generated mice harboring germline mutations in which the enhancer element located 9 kb 3' of the immunoglobulin kappa light chain gene (3'E kappa) was replaced either by a single loxP site (3'E kappa delta) or by a neomycin resistance gene (3'E kappa N). Mice homozygous for the 3'E(kappa delta) mutation had substantially reduced numbers of kappa-expressing B cells and increased numbers of lambda-expressing B cells accompanied by decreased kappa versus lambda gene rearrangement. In these mutant mice, kappa expression was reduced in resting B cells, but was normal in activated B cells.

Role of light chain variable region in myeloma with light chain deposition disease: evidence from an experimental model.

Light chain deposition disease (LCDD) results from a propensity of some human monoclonal L chains to form tissue deposits. We designed an experimental model for in vivo expression of human kappa L chain sequences in mice and compared a somatically mutated LCDD chain with a closely related control kappa chain, both encoded by the unique V kappa IV gene. Mice secreting the LCDD chain but not those producing the control chain showed deposits with a distribution similar to that observed in patients.

Sequences of V kappa L subgroup light chains in Fanconi's syndrome. Light chain V region gene usage restriction and peculiarities in myeloma-associated Fanconi's syndrome.

Certain monoclonal Ig light chains (LC) are responsible for marked disturbances of proximal tubule cell functions (Fanconi's syndrome, FS). In patients with FS, intracellular crystal-like inclusions containing LC determinants are commonly found in plasma cells, macrophages, and renal tubular cells. In an attempt at understanding the pathogenesis of myeloma-associated FS, we recently determined the first complete primary sequence of a kappa-LC (CHEB) responsible for the disease.

Structure of abnormal heavy chains in human heavy-chain-deposition disease.

The sequences of two immunoglobulin gamma 1 heavy chains involved in the formation of non-amyloid tissue deposits were determined in two patients (RIC and THR) affected with plasma cell monoclonal proliferation and heavy-chain-deposition disease. The proliferating plasma cells of patients RIC and THR synthesized truncated gamma 1 chains of 45 kDa and 24 kDa, respectively, carrying internal deletions of the first constant (CH1) domain (RIC) or of the CH1, hinge and CH2 domains(THR). The shortened gamma chains were associated with lambda light chains in the monoclonal IgG component present in the serum from both patients but not in tissue deposits which lacked any detectable light chains.

Intramuscular injections of slow-release lanreotide (BIM 23014) in acromegalic patients previously treated with continuous subcutaneous infusion of octreotide (SMS 201-995).

Nine acromegalic patients (five females and four males), mean age 50 +/- 4 years, presented macroadenomas (N = 7), microadenoma (N = 1) or normal computed tomography scans (N = 1). Patients were treated with continuous subcutaneous infusion of octreotide (range 200-600 micrograms/day). Following a washout period of 7 days, the patients were injected im with 30 mg slow-release lanreotide every 10 days for the first month and then twice monthly.

The effect of intron sequences on expression levels of Ig cDNAs.

Several cDNA expression vectors were constructed and tested by stable transfection into a murine lymphoid cell line in order to compare secretion rates of a human immunoglobulin (Ig) light chain (LC). When the cDNA was under transcriptional control of the SV40 promoter and enhancer and preceded by the SV40 19S late mRNA intron, a weak LC production was detected. Secretion rate was not improved by replacing the SV40 promoter and enhancer by a combination of a murine Ig heavy chain (HC) gene promoter and enhancer even with insertion of additional Ig enhancers.

A class switch control region at the 3' end of the immunoglobulin heavy chain locus.

We replaced the IgH 3' enhancer (3'EH) region with a neomycin resistance gene in ES cells and generated chimeric mice in which all mature lymphocytes were either heterozygous (3'EH+/-) or homozygous (3'EH-/-) for the mutation. In vitro activated 3'EH-/- B cells responded similarly to 3'EH+/- B cells with respect to proliferation and secretion of IgM and IgG1 but were specifically deficient in IgG2a, IgG2b, IgG3, and IgE secretion. These isotype deficiencies correlated with a deficiency in accumulation of transcripts from and class switching to affected CH genes.

Monoclonal immunoglobulin deposition disease: a review of immunoglobulin chain alterations.

Monoclonal immunoglobulin deposition disease, a complication of overtly malignant or apparently benign immunoproliferative disorders, is a severe disease featuring tissue deposition of monoclonal light, light and heavy, or heavy chains. A number of converging arguments strongly suggest a direct pathogenetic role of structural abnormalities or peculiarities of variables regions of light and/or heavy chains (associated with deletions in the constant region for the heavy chains). Recent structural data on these abnormal immunoglobulin chains are reviewed.

Molecular remission after allogeneic bone marrow transplantation for chronic lymphocytic leukemia.

A 51-year-old man with previously treated CLL received an allogeneic sex mismatched BMT after total body irradiation and high dose chemotherapy. Residual disease was studied at phenotypic and molecular levels including Y chromosome DNA amplification by PCR assay. The patient was clinically disease-free 20 months after BMT with disappearance of the leukemic clone assessed by the most sensitive methods of detection.

Androgenic granulosa cell tumor of the ovary: in vivo hormonal studies.

Androgenic granulosa cell tumors of the ovary are rare and have not been well studied hormonally. A 20-year-old woman complaining of secondary amenorrhea with high plasma testosterone (295 ng/dl) and a right ovarian tumor was studied. Plasma testosterone levels decreased after two days of dexamethasone (36 ng/dl), increased after hCG administration (538 ng/dl) and a unilateral right ovarian gradient of testosterone was noted at the selective catheterization of ovarian veins.

Complete variable region deletion in a mu heavy chain disease protein (ROUL). Correlation with light chain secretion.

In a patient affected with chronic lymphocytic leukemia with lymphocyte surface mu and kappa determinants and vacuolated bone marrow plasma cells, the serum contained polymers of a truncated mu chain and normal-sized kappa chains. These light chains were present as monomers and covalent dimers in studies performed under dissociating conditions, but they were linked by non-covalent bridges to a portion of the serum short mu chains. The patient's urine contained a kappa type Bence-Jones protein.

Exon skipping without splice site mutation accounting for abnormal immunoglobulin chains in nonsecretory human myeloma.

The proliferating plasma cells of patient COM with nonsecretory myeloma synthesized truncated 42 kDa gamma 1 chains made of a complete constant region but devoid of variable domain. In the absence of light chain expression, the shortened gamma chains were retained intracellularly and were subsequently degraded within 12 h. COM neoplastic plasma cells contained short gamma 1 heavy chain transcripts in which the leader peptide exon was directly joined to the CH1 exon using the regular splice sites.

Cellular localization of hydroxyindole-O-methyltransferase mRNA in the chicken pineal gland.

Hydroxyindole-O-methyltransferase (HIOMT), is the last enzyme of the melatonin biosynthesis pathway. We have applied immunocytochemistry and in situ hybridization to localize HIOMT producing cells, in the chicken epithalamus including the pineal gland. The selectivity of the hybridization signal over melatoninergic cells was ascertained by comparison with the immunolabelling.

Monoclonal Ig L chain and L chain V domain fragment crystallization in myeloma-associated Fanconi's syndrome.

Monoclonal free L chains secreted in immunoproliferative disorders are frequently involved in renal complications, including a specific proximal tubule impairment, the Fanconi's syndrome, which is generally featured by intracellular crystallization of L chain-related material. In a patient with myeloma-associated Fanconi's syndrome, hexagonal crystals (most surrounded by smooth membranes) were found in kidney proximal tubular cells and bone marrow plasma cells and phagocytes. The sequence of the patient's monoclonal kappa-chain was deduced from that of identical kappa-cDNA clones from the tumoral plasma cells.

Transcriptional regulation of hydroxyindole O-methyltransferase in the chicken pineal gland: day/night changes and long-term effects of light and darkness.

The indolic hormone melatonin is produced by the pineal gland according to a daily rhythm. The terminal step of melatonin synthesis is catalysed by hydroxyindole O-methyltransferase (HIOMT, EC 2.1.

Primary structure of a variable region of the V kappa I subgroup (ISE) in light chain deposition disease.

Although structural abnormalities of monoclonal immunoglobulin light chains (LC) are suspected to play a determinant role in non-amyloid light chain deposition disease (LCDD), this condition is as yet poorly documented at the molecular level, since only three sequences have been reported to date. In a case of myeloma-associated LCDD, the patient's urine contained an unglycosylated kappa Bence Jones protein made up of dimers and monomers with an apparent molecular mass of 25,000 which was assigned to the V kappa I subgroup by N-terminal amino acid sequencing. The complete variable region sequence of the monoclonal kappa chain produced by the malignant plasma cells was amplified by polymerase chain reaction (PCR) using small amounts of material obtained by bone marrow aspiration.

A human myeloma IgA with a hybrid heavy chain resulting from putative somatic gene conversion.

A human monoclonal IgA1-IgA2 lambda hybrid molecule was detected in a myeloma patient homozygous for the A2m(1) allotype during a systematic study of monoclonal IgA with subclass-specific monoclonal antibodies (mAb) and the lectin jacalin. This monoclonal immunoglobulin (GAU) reacted with both, although not with all, anti-alpha 1 and anti-alpha 2 mAb. Its heavy (H) chain contained an alpha 1 hinge region as shown by jacalin reactivity, the presence of disulfide-linked H and light chains in spite of its belonging to the IgA2m(1) allotype and amino acid composition of the isolated hinge region.

[Transcriptional regulation of an enzyme involved in the synthesis of melatonin].

The indolic hormone melatonin is produced by the pineal gland according to a daily rhythm. The terminal step of melatonin synthesis is catalyzed by hydroxyindole-O-methyltransferase (HIOMT, EC 2.1.

[Hyperthyroidism caused by inappropriate secretion of TSH. Apropos of 2 new cases].

Hyperthyroidism due to inappropriate secretion of TSH is rare. It may be due to either TSH-secreting pituitary adenomas (n = 15) or selective pituitary resistance to thyroid hormone action (n = 31). The recognition of these patients is of great clinical importance since they should be treated differently than patients with more common forms of hyperthyroidism (Graves' disease, autonomous thyroid nodule).

Structure and expression of the mb-1 transcript in human lymphoid cells.

The mb-1 gene encodes a protein associated with membrane-bound immunoglobulins (mIg) and it has been suggested that it may play a role in signal transduction. Using a murine probe, we cloned a human complementary DNA homologous to the murine mb-1 sequence. Its complete sequence is in full agreement with a recently published human cDNA sequence but differs from a previously reported partial sequence.

Complementary DNA sequence of human amyloidogenic immunoglobulin light-chain precursors.

The primary structure of three amyloid precursor light chains was deduced from the sequence of complementary DNA (cDNA) from bone marrow cells from patients affected with classical lambda (patient Air) or kappa (patient Arn) amyloidosis and from a patient (Aub) in whom lambda amyloid deposits were unusual by their perimembranous location in the kidney glomerulus. All three RNAs were of normal size, as estimated by Northern blotting, and encoded normal-sized light chains. The deduced light-chain sequence from patient Arn was related to the V kappa 1 subgroup, and included ten residues that had not been previously reported at these positions, only one of which (Leu-21) was located in a beta-sheet (4-2).