Monoclonal Proliferation Of Lymphocytes Research Articles

MO232: Amyloidosis AL in Nephrology

Abstract BACKGROUND AND AIMS Systemic AL amyloidosis is a rare pathology associated with the precipitation of monoclonal immunoglobulin light chains in the form of fibrils in various organs. Clinical presentations are extremely variable and diagnosis is often delayed. The two most affected organs are the kidney and the heart. The treatment is based on chemotherapy to eliminate the medullary clone that produces the monoclonal light chain. However, the outcome is still poor. The aim of our study was to describe the demographic, clinicobiological, histological, therapeutic and evolutionary characteristics of AL amyloidosis in our population. METHOD We carried out a single-center retrospective descriptive trial of patients who were diagnosed with histologically confirmed AL amyloidosis in our Nephrology Department during the period from 2014 to 2021. RESULTS We enrolled 12 patients with a mean age of 61.25 ± 8.17years. The sex ratio (M/F) was 3. The histological confirmation of AL amyloidosis was based on biopsies: kidney (n = 7) and salivary glands (n = 5). The immunoglobulin type was Ig G Lambda in 75% of cases (n = 9), IgG kappa in 16.6% of cases (n = 2) and IgM in 8.3% of cases (n = 1). The cause of amyloidosis was multiple myeloma in 66.6% of cases (n = 8) and Waldenström disease in 8.3% of cases (n = 1). The mean creatinine at diagnosis was 441.33 ± 334.47 umol/L, i.e. a median creatinine clearance (MDRD) of 36.67 ± 46.77 mL/min. At the time of diagnosis, 50% of the patients (n = 6) had end-stage renal disease and 25% (n = 3) had reached it after a few more months. The mean proteinuria was 6.33 g/24 h within 83.3% of cases (n = 10) with the presence of a nephrotic syndrome. The cardiac involvement was found in 58% of the patients (n = 7) at the time of diagnosis with a Mayo Clinic prognostic score of III. The neurological involvement was observed in 8.3% of cases (n = 1) and was confirmed by spinal MRI as polyradiculoneuritis. As for the therapeutical management, 75% of the patients (n = 9) received first-line treatment with Bortezomib Cyclophosphamide Dexamethasone, and 16.6 of the patients (n = 2) were treated with corticosteroids and Melphalan (the 12th patient died early). The outcome was fatal in 41.5% (n = 5) and the cause of death was a state of septic shock, and the rest of the patients are alive with a mean follow-up of 1 year. CONCLUSION AL Amyloidosis is one of the most severe complications of monoclonal lymphocyte proliferation. This overgrowth is most frequently related to myeloma, and rarely to another malignant B-cell disease. The prognosis is related to cardiac and renal impairment. It requires urgent management to improve its outcome and to reduce mortality.

Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas.

Primary central nervous system lymphomas (PCNSLs) are angiocentric neoplasia which present dense monoclonal lymphocyte proliferation, and occur in brain parenchyma in 90% of the cases. Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL) subtype represents more than 90% of PCNSLs and is the most aggressive subtype with a cure rate of only 40%. One of the characteristics of ABC-DLBCL subtype is neuroinflammation through the activation of NF-kappaB pathway. c-Myc alterations and protein expression have been shown in aggressive DLBCL. c-Myc is considered as a key prognostic and predictive biomarker for survival in DLBCL, its expression is associated with worst survival rates. Although mRNA of c-Myc is increased by low levels gains of c-Myc, several studies have shown that c-Myc protein expression is overexpressed without c-Myc abnormalities. These high levels of c-Myc protein in DLBCL without genetic abnormalities suggest that c-Myc protein expression may be also increased by other mechanisms or signaling pathways which regulate its expression. In PCNSLs, the canonical WNT/beta- catenin pathway is upregulated while PPAR gamma is downregulated. The opposite interplay between WNT/beta-catenin pathway and PPAR gamma is reviewed here. Activation of WNT/beta-catenin pathway leads to the transcription of genes involved in cell proliferation, mitochondrial metabolism, protein synthesis, and tumor growth, such as c-Myc. PPAR gamma agonists induce the inhibition of several signaling pathways such as NF-kappaB, STAT, PI3K/Akt and WNT/beta-catenin pathway. Activation of PPAR gamma agonists may have a major negative key role in the regulation of PCNSLs progression.

Poststreptococcal syndrome mimicking conjunctival lymphoma

BackgroundPoststreptococcal syndrome (PSS) can be a consequence of nonpurulent primary infection with group A streptococci (GAS). Postreptococcal uveitis is a well recognized entity with quite a few descriptions in the literature, but so far no conjunctival involvement has been reported.The aim of the study is to present a rare case of postreptococcal conjunctival lesions mimicking a lymphoma.Case presentation19-years-old Caucasian female presented with pink, nodular infiltrates in the right conjunctiva that occurred a few months after upper respiratory tract infection and tonsillectomy. Histopathological examination of collected lesion samples revealed inflammatory reaction with lymphocytes proliferation and failed to rule out a myeloma. Complementary flow-cytometry did not show monoclonal proliferation of lymphocytes B. During follow-up we observed the complete regression of conjunctival lesions after the benzyl penicillin treatment prescribed by ENT specialist due to elevated plasma ASO levels. Therefore, we suppose that those lesions must have represented a part of poststreptococcal syndrome.ConclusionsTo conclude, this is, to the best of our knowledge, the first report of conjunctival involvement in the course of PSS related to group A streptococci.

A Defect of the INK4-Cdk4 Checkpoint and Myc Collaborate in Blastoid Mantle Cell Lymphoma–Like Lymphoma Formation in Mice

Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a monoclonal proliferation of lymphocytes with the co-expression of CD5 and CD43, but not of CD23. Typical MCL is associated with overexpression of cyclin D1, and blastoid MCL variants are associated with Myc (alias c-myc) translocations. In this study, we developed a murine model of MCL-like lymphoma by crossing Cdk4(R24C) mice with Myc-3'RR transgenic mice. The Cdk4(R24C) mouse is a knockin strain that expresses a Cdk4 protein that is resistant to inhibition by p16(INK4a) as well as other INK4 family members. Ablation of INK4 control on Cdk4 does not affect lymphomagenesis, B-cell maturation, and functions in Cdk4(R24C) mice. Additionally, B cells were normal in numbers, cell cycle activity, mitogen responsiveness, and Ig synthesis in response to activation. By contrast, breeding Cdk4(R24C) mice with Myc-3'RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma (CD19(+)IgM(+)IgD(+) cells) leads to the development of clonal blastoid MCL-like lymphoma (CD19(+)IgM(+)CD5(+)CD43(+)CD23(-) cells) in Myc/Cdk4(R24C) mice. Western blot analysis revealed high amounts of Cdk4/cyclin D1 complexes as the main hallmark of these lymphomas. These results indicate that although silent in nonmalignant B cells, a defect in the INK4-Cdk4 checkpoint can participate in lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation that might be reminiscent of the development of human blastoid MCL.

Large Granular Lymphocyte Leukemia: Clonality Reconsidered.

Background: T-cell large granular lymphocyte (LGL) leukemia is widely considered to represent a monoclonal proliferation of lymphocytes. Clonality assessment methods have evolved from Southern blots (first-generation) to polymerase chain reaction with heteroduplex electrophoresis (second-generation) to high-resolution capillary electrophoresis (third-generation) testing.Aims: To determine if third-generation T-cell clonality assays result in a higher frequency of oligoclonal results, to compare the concordance for testing at the T-cell receptor (TCR) gamma (TCRG) and TCR beta (TCRB) loci, and to compare the clinical characteristics of patients with monoclonal vs. oligoclonal TCRs.Methods: The study population consisted of patients from August 1999-April 2007 with elevated circulating LGLs and cytopenia(s). TCRG locus clonality was determined by both the heteroduplex method and capillary electrophoresis in 35 patients. 89 samples were tested for TCRG and TCRB clonality using the Biomed II PCR primer sets and capillary electrophoresis on an ABI 3100 automated DNA sequencer. Determinations of clonality were made independently by three pathologists blinded to the clinical characteristics of the patients.Results: A total of 93 patients (median age 50 years, 53% female) were evaluated. Median absolute neutrophil count was 1.56 × 109/L (range 0.2–7.8 × 109/L), median lymphocyte count was 1.81 × 109/L (range 0.6–13 × 109/L), and median hemoglobin was 13 g/dL (range 6.3–17.4 g/dL). The concordance rate for TCRG clonality testing by the heteroduplex and capillary electrophoresis methods was only 40%. The primary difference was a striking increase in the frequency of oligoclonal results by the capillary electrophoresis method (p= 0.00007). All of these samples appeared monoclonal by the lower resolution heteroduplex assay (Table 1). Concordance for clonality for TCRG vs. TCRB was 54% (Table 2). All samples had monoclonality or oligoclonality demonstrated at TCRG or TCRB, but only 26% were monoclonal at both loci. The clinical characteristics for the 23 patients with monoclonal TCRG and TCRB appeared similar to the 23 patients with oligoclonal TCRG and TCRB. The median age in both groups was 53 years, with 61% of patients in each group requiring treatment after a median of 36.8 and 38.6 months of follow-up, respectively.Discussion: The high resolution of capillary electrophoresis appears to result in a much greater proportion of oligoclonal TCRG results, which by the older heteroduplex method would have been considered monoclonal. Furthermore, the concordance rate at TCRG and TCRB appears to be remarkably low. Though oligoclonal T-cell populations are generally believed to be transient and reactive processes, the clinical characteristics of our oligoclonal and monoclonal cohorts did not differ significantly.Conclusion: Capillary electrophoresis frequently identifies patients with oligoclonal TCR whose clinical features are indistinguishable from those of patients with classic monoclonal LGL leukemia.HeteroduplexMonoclonalNegativeOligoclonalTotalMonoclonal121114Capillary ElectrophoresisNegative4206Oligoclonal150015Total313135TCRGMonoclonalNegativeOligoclonalTotalMonoclonal2331238TCRBNegative7018Oligoclonal1532543Total4563889

The differentiation of idiopathic inflammatory pseudotumor from lymphoid tumors of orbit: Analysis of 319 cases

purpose To analyze the clinical, morphologic, immunophenotypic, and molecular genetic differences between idiopathic inflammatory pseudotumor and lymphoid tumors of the orbit. methods 209 patients with IOIP and 110 patients with lymphoid tumors seen between January 1, 1978 and December 31, 1999 in Zhongshan Ophthalmic Center, Sun Yat-sen University were evaluated retrospectively. results More patients with lymphoid tumors had palpable mass than patients with idiopathic orbital inflammatory pseudotumor (IOIP) (P < 0.0001), with the percentage of 90% and 65%, respectively, whereas more patients with IOIP had swollen eyelid, eyelid or conjunctival congestion, pain, retinal folds or hamorrhage, and optic nerve atrophy than patients with lymphoid tumors, with the percentage of 55% and 40% (P = 0.014), 42% and 24% (P = 0.001), 24% and 1% (P < 0.0001), 14% and 4% (P = 0.004), 7% and 2% (P = 0.043), respectively. Ultrasound and computed tomography/magnetic resonance image (CT/MRI) scan usually could not differentiate IOIP from lymphoma. Nearly one third of patients with IOIP could not be easily differentiated pathologically from lymphoid tumor. Immunophenotypic, and molecular genetic analyses can differentiate IOIP from lymphoid tumor based on polyclonal or monoclonal proliferation of lymphocytes with the IOIP being polyclonal and lymphoma monoclonal. conclusions Idiopathic orbital inflammatory pseudotumor and lymphoid tumor showed distinguishing clinical, morphologic, immunophenotypic, and molecular genetic characteristics.

A scoring system for the classification of CD5-B CLL versus CD5+ B CLL and B PLL.

B CLL is a monoclonal proliferation of lymphocytes which express the CD5 antigen (CD5+ CLL). Rare exceptions (less than 10%) are CD5-, as are the majority of B PLL. We have studied the clinical, cytological and immunophenotypic characteristics of a series of 12 CD5-CLL and have established a score which allows the distinction between CD5+ CLL, CD5- CLL and PLL. Among the CD5- CLL, there were significantly more cases with advanced stage (Rai and Binet) and splenomegaly. The cytological study found more mixed CLL according to FAB classification (more prolymphocytes). There were significantly more CD23-, FMC7+, SIg strong positive cases. A score from 0 to 6 was established based on clinical, cytological and immunophenotypic criteria. Typical CD5+ CLL was scored 0, score 6 corresponded to typical PLL. There were significantly more higher scores amongst CD5- CLL. It therefore appears that CD5- CLLs share certain features with B PLL. The use of this scoring system will allow determination of prognosis within these different categories, thus identifying groups which require specific therapy.

リンパ球増殖を伴った咽頭病変の２症例

Malignant lymphomas are not rare in the otorhinolaryngological region. We report two cases of lymphoproliferative disorder initially suspected as malignant. In immunological stains of both frozen and paraffin sections, monoclonal lymphocyte proliferation was not confirmed.Moreover, Southern blot analysis did not show JH and TCR-β gene rearranged bands, although both patients had abnormal chromosomal patterns. Three possible theories are presented to account for these paradoxical data. 1) The amount of tissue for histological study and for Southern blot was inadequate; 2) the enzymes used in the Southern blot test were unsuitable in these cases; 3) mutation occurred before gene rearrangement. The last is the most reasonable explanation.Should these cases be regarded as malignant? Radiation and chemotherapy were effective in these patients, and these treatments are not thought to be a poor first choice. We emphasize the importance of careful studies of these border-malignant disorders when the histological findings cannot prove monoclonal proliferation.

Demonstration of clonal proliferation of T lymphocytes in early neoplastic disease: Studies with probes for the β-chain of the T cell receptor and human T cell lymphotropic virus type I

This study demonstrates that the detection of rearrangement of the T-cell receptor gene and adult T cell leukemia virus or human T cell lymphotropic virus type I (ATLV/HTLV-I) integration in the genome are sensitive and practical methods for the diagnosis and characterization of cutaneous T cell neoplasms. Biopsy specimens obtained from small skin nodules containing a dense infiltration of lymphocytes were analyzed by Southern blotting with the use of probes for both the β-chain of the T-cell receptor gene and the ATLV/HTLV-I genome. DNA samples from one patient with early, chronic adult T cell lymphoma or leukemia, revealed the monoclonal proliferation of lymphocytes. For another patient with early cutaneous T cell lymphoma analysis by Southern blotting with the β-chain probe of DNA from three separate lesions revealed identical rearranged bands, indicating not only the monoclonal proliferation of T cells in each lesion but also the clonal origin of each lesion. In contrast, analysis by Southern blotting of DNA samples extracted from three nodules from a patient with lymphomatoid papulosis showed no rearranged band and therefore no clonal proliferation. DNA extracted from blood lymphocytes of these patients failed to hybridize with the probes described above as a rearranged band. These results indicate that analysis of DNA extracted from skin lesions may have diagnostic value in determining monoclonal proliferation of lymphocytes in patients with early stage cutaneous lymphomas.

The correlation between the direct and indirect detection of bovine leukemia virus infection in cattle

Ninety-three cattle from a herd naturally infected with bovine leukemia virus (BLV) were tested for the presence of BLV infection by two indirect indicators, anti-BLV antibodies and lymphocytosis, and two direct indicators, BLV provirus and BLV gp51 antigen expression in peripheral blood mononuclear cells (PBMC). Forty-eight percent (45/93) of the cattle were seropositive, and of these, 53% (24/45) were provirus-positive. Freshly isolated PBMC were negative for gp51 antigen expression, but 11 cattle were positive following short-term culture of their PBMC; 10 of these were seropositive/provirus-positive cattle, and one was a seropositive/provirus-negative cow. Lymphocytosis was present in eight cattle, all of which were seropositive/provirus-positive/gp51-positive. Four cattle were provirus-positive, but negative for all other indicators of BLV infection; a second blood sample was collected from three of these cattle at a later date, at which time two of the three had seroconverted. These results suggest that depending on the stage of the infection, the pathogenesis of BLV in cattle may involve fundamental differences in the host-viral relationship, including the number of cells infected or the number of copies of integrated provirus per cell, regulation of expression of viral antigens, induction of the anti-viral immune response, and the polyclonal or monoclonal proliferation of lymphocytes.

Neuropathy and anti‐myelin‐associated glycoprotein IgM M proteins: T cell regulation of M protein secretion in vitro

In patients with plasma cell dyscrasia, individual clones of antibody-producing cells proliferate abnormally and secrete monoclonal antibodies or M proteins in excess. The cause of the monoclonal proliferation of lymphocytes and M protein secretion is unknown and it is not known whether the M protein-secreting B cells are autonomous or capable of responding to regulatory T cells. We carried out experiments using lymphocytes from a patient with neuropathy and plasma cell dyscrasia whose IgM M protein bound to the myelin-associated glycoprotein (MAG) to determine whether secretion of the M protein in vitro was responsive to T cell help or suppression. M protein secretion was measured by an enzyme-linked immunosorbent assay system for measuring anti-MAG IgM, and the number of M protein-secreting lymphocytes was enumerated by a reverse hemolytic plaque assay specific for the M protein idiotype. The patient's B cells were maximally stimulated by pokeweed mitogen-activated autologous OKT4+ T-helper cells and the helper effect was inhibited by OKT8+ suppressor/cytotoxic T cells. Low levels of M protein secretion in the absence of T cells were also observed and there was partial stimulation of M protein secretion by T cells in the absence of pokeweed mitogen.

Lymphoproliferative disease in severe combined immunodeficiency

A 7 month-old-boy with severe combined immunodeficiency suffered from cough, diarrhea, and intractable candidiasis, and died of a respiratory failure by giant cell pnemonia at 13 month-old. Immunological studies revealed low numbers of T cells, poor responses of his lymphocytes to mitogens, and markedly increased levels of surface immunoglobulin bearing cells. Serum concentrations of IgA and IgM were normal and IgG was high with M component, but functional antibody responses were absent. A plasma cell was absent in bone marrow and lymph nodes at autopsy. It was suggested that the maturation of B cell to plasma cell was impaired.In addition, a tumor was found at his left upper arm on admission. The biopsy revealed that the tumor was a lymphoproliferative disease and consisted of the cells resembled mature lymphocytes. None of cells formed E rosette and had the surface immunoglobulin. The tumor cells infiltrated the muscles and fractured the left humerus. However, the tumor regressed spontaneously. At autopsy, the tumor was not found at the left upper arm but a solitary tumor with lymphoproliferation was found in the liver. It can not be denied that transfer factor and transplanted fetal thymus had an effect on the tumor regression. It is suggested that the tumor was not malignant but a monoclonal lymphocyte proliferation responsed to certain stimuli. Transplantations of the fetal thymus and the liver were unsuccesful in restoring immunity.

B lymphocytes in untreated patients with malignant lymphoma and Hodgkin's disease.

B and T lymphocytes in 37 untreated patients with malignant lymphoma and Hodgkin's disease were studied. B cells in the peripheral blood were investigated with respect to surface immunoglobulins and in a few patients with respect to intracytoplasmic immunoglobulins by means of immunofluorescence. T cell function was studied by direct phytohemagglutinin (PHA) microtest (from the same sample of whole blood), mixed lymphocyte culture (MLC), and by delayed hypersensitivity to various antigens. In the 13 patients with Hodgkin's disease the histologic subtype was nodular sclerosis in nine, lymphocyte predominant in two, mixed cellularity in two. Only one of these patients had disseminated disease (stage IV); he showed impaired cellular immunity, a very low percentage of B cells and low levels of serum immunoglobulins. Of the remaining patients with Hodgkin's disease, with one exception, normal percentages but rather low absolute numbers of B lymphocytes per mm(3) of blood were found. One patient with a low percent and low absolute number of B lymphocytes showed very high serum IgG. Of 24 patients with non-Hodgkin's malignant lymphoma, seven (29%) showed monoclonal B cell proliferation in the peripheral blood (five mukappa, two gammakappa). By morphologic criteria, 14 patients had involvement of bone marrow, five of these had involvement of peripheral blood. Four of the latter five patients showed marked increases in percentages and absolute numbers of B lymphocytes in the peripheral blood reflecting the monoclonal proliferation. In three additional patients monoclonal proliferation of lymphocytes was found by immunofluorescence although the blood smears appeared morphologically normal. Serum immunoglobulin abnormalities without monoclonal B cell proliferation in the peripheral blood were observed in six patients.