TOX as a new diagnostic marker for T cell large granular lymphocytic leukaemia.

AIMS: T cell large granular lymphocytic leukaemia (T-LGLL) is a rare disorder that may underlie otherwise unexplained cytopenias. The identification of T-LGLL cells in bone marrow biopsies can be a challenge, because a robust immunohistochemistry marker is lacking. The markers currently in use (granzyme B, TIA-1 and CD8) are difficult to interpret or lack specificity. Therefore, we investigated whether immunohistochemistry for thymocyte selection-associated high-mobility group box (TOX), a transcription factor that associates with chronic T cell stimulation, could be a reliable tool for the identification of T-LGLL cells. METHODS AND RESULTS: In this retrospective study, expression of TOX in CD8+ cells in bone marrow biopsies of T-LGLL patients (n = 38) was investigated and compared to bone marrow of controls with reactive T cell lymphocytosis (n = 10). All biopsies were evaluated for TOX staining within the CD8-positive T cell population. The controls were essentially negative for TOX, whereas all T-LGLL cases were positive (median = 80%, range = 10-100%), even when bone marrow involvement was subtle. CONCLUSION: TOX is a highly sensitive marker for the neoplastic cells of T-LGLL and we recommend its use, especially in the diagnostic work-up of patients with unexplained cytopenias.

Ectopic pleural thymoma with T-cell lymphocytosis and bone metastasis: a case report.

BACKGROUND: The diagnostic complexities that arise in radiographic distinction between ectopic pleural thymoma and other thoracic neoplasms are substantial, with instances of co-occurring T-cell lymphocytosis and osseous metastasis being exceedingly rare. CASE PRESENTATION: A 51-year-old woman was admitted to our hospital with dyspnea and chest pain. Upon imaging examination, she was found to have diffuse and nodular pleural thickening on the left side, collapse of the left lung and a compression in the second thoracic vertebrae. All lesions showed significant 18F-FDG uptake on 18F-FDG PET/CT examination. Furthermore, she exhibited T-cell lymphocytosis in her peripheral blood, lymph nodes, and bone marrow. After ruling out malignant pleural mesothelioma (MPM), lung cancer with pleural metastasis, and T-cell lymphoma, the definitive diagnosis asserted was ectopic pleural thymoma with T-cell lymphocytosis and bone metastasis. CONCLUSION: Physicians need to expand their knowledge of the imaging features of ectopic pleural thymoma. Cases with T-cell lymphocytosis may exhibit increased aggressiveness and prone to bone metastasis.

Intestinal Epithelial Digestive, Transport, and Barrier Protein Expression Is Increased in Environmental Enteric Dysfunction.

Environmental enteric dysfunction (EED) is characterized by malabsorption and diarrhea that result in irreversible deficits in physical and intellectual growth. We sought to define the expression of transport and tight junction proteins by quantitative analysis of duodenal biopsies from patients with EED. Biopsies from Pakistani children with confirmed EED diagnoses were compared to those from age-matched North American healthy controls, patients with celiac disease, and patients with nonceliac disease with villous atrophy or intraepithelial lymphocytosis. Expression of brush border digestive and transport proteins and paracellular (tight junction) proteins was assessed by quantitative multiplex immunofluorescence microscopy. EED was characterized by partial villous atrophy and marked intraepithelial lymphocytosis. Epithelial proliferation and enteroendocrine, tuft, and Paneth cell numbers were unchanged, but there was significant goblet cell expansion in EED biopsies. Expression of proteins involved in nutrient and water absorption and that of the basolateral Cl- transport protein NKCC1 were also increased in EED. Finally, the barrier-forming tight junction protein claudin-4 (CLDN4) was significantly upregulated in EED, particularly within villous enterocytes. In contrast, expression of CFTR, CLDN2, CLDN15, JAM-A, occludin, ZO-1, and E-cadherin was unchanged. Upregulation of a barrier-forming tight junction protein and brush border and basolateral membrane proteins that support nutrient and water transport in EED is paradoxical, as their increased expression would be expected to be correlated with increased intestinal barrier function and enhanced absorption, respectively. These data suggest that EED activates adaptive intestinal epithelial responses to enhance nutrient absorption but that these changes are insufficient to restore health.

Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

From the archives of MD Anderson Cancer Center: Aleukemic T-prolymphocytic leukemia, a rare presentation and review of the literature.

T-prolymphocytic leukemia (T-PLL) is a rare, aggressive T-cell leukemia, and patients typically present with marked peripheral blood lymphocytosis. Approximately 15-20 % of patients may present with moderate and relative stable lymphocytosis and an indolent clinical course that can persist for a few years. However, eventually these patients go on to develop marked lymphocytosis and rapidly progressive disease. We report a 72-year-old man who presented with multicompartmental lymphadenopathy and a normal complete blood count. Excision of left and right cervical lymph nodes showed replacement of the lymph node architecture by a small T-cell neoplasm positive for CD3, CD4, CD5, CD7 and TCL-1, and negative for CD8, CD20, CD30 and ALK. Subsequent bone marrow evaluation showed minimal bone marrow involvement by a T-cell neoplasm associated with TCL1A rearrangement in 11 % of cells supporting the diagnosis of T-PLL. Despite treatment, he showed progressive lymphadenopathy while remarkably maintaining normal white blood cell counts until he eventually developed leukocytosis of 110.9 × 103/uL 26 months later. Review of the literature identified only a single abstract reporting a patient with a similar lymphoma-like presentation and normal white blood cell count; however, that case showed significant bone marrow involvement in stark contrast to the current case. In summary, we report a highly unusual case of T-PLL can initially presenting with an aleukemic or lymphoma-like clinical picture, which can make establishing the diagnosis challenging.

Clinico-Haematological Profile Of Chronic Lymphoproliferative Disorders In Patients Presenting With Lymphocytosis.

Objectives: To assess the spectrum and clinico-haematological profile of chronic lymphoproliferative disorders in patients presenting with lymphocytosis. METHODS: The cross-sectional, retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data related to cases of bone marrow aspirate and trephine from January to November 2020. Patients for whom the bone marrow was done for lymphocytosis were studied for the presence of lymphoproliferative disorders, sub-types and patients'characteristics. The diagnosis and classification were based on the World Health Organisation criteria for tumours of haematopoietic and lymphoid tissues. Data was analysed using SPSS 21. RESULTS: Of the 3,334 bone marrow specimenstested, 103(3%) were related to lymphocytosis. Of these, 84(82%) were diagnosed with lymphoproliferative disorders, while diagnosisremained undetermined in 19(18%) cases. Male:female ratio was 3.6:1 and median age was 60 years (range: 21-85 years). Constitutional symptoms were found in 61(73%) patients. Median absolute lymphocyte count was 45x109/L (range: 5.3-480). All 84(100%) patients were classified as B-cell lymphoproliferative disorder. Chronic lymphocytic leukaemia wasthe most common form, 61(73%), and 31(51%) of them presented with advanced stage disease. CONCLUSIONS: A huge majority of patients presenting with lymphocytosis had underlying lymphoproliferative disorders of which B-cell chronic lymphocytic leukaemia was found to be the most common.

Immunophenotyping of intraepithelial lymphocytes in canine chronic enteropathy and intestinal T-cell lymphoma using endoscopic samples.

Human enteropathy-associated T-cell lymphoma (EATL) is considered to be derived from intraepithelial lymphocytes (IELs); however, the origin of canine intestinal T-cell lymphoma (ITCL) remains unclear. Histological, immunohistochemical, and clonality examinations were performed using endoscopically collected canine duodenum samples of mucosal lesions of chronic enteropathy (CE; 73 cases) and ITCL without transmural neoplastic mass lesions (64 cases). Histopathological examinations revealed the intraepithelial accumulation of lymphocytes (called "intraepithelial lymphocytosis") in 54/73 CE cases (74%) and the epitheliotropism of neoplastic lymphocytes in 63/64 ITCL cases (98%). Immunohistochemically, IELs in CE with intraepithelial lymphocytosis (IEL+CE) were diffusely immunopositive for CD3, with scattered immunopositivity for CD5, CD8, CD20, and granzyme B (GRB). The percentage of CD8+ in CD3+ IELs was significantly lower in IEL+CE than in CE without intraepithelial lymphocytosis (IEL-CE). Double-labeling immunohistochemistry revealed a high percentage of GRB expression in CD8- IEL among IEL+CE. Among 64 ITCL cases, CD3 was immunopositive in 64 (100%), CD5 in 22 (34%), CD8 in 8 (13%), CD20 in 12 (19%), CD30 in 13 (20%), and GRB in 49 (77%). In CD3+ cells, Ki67 immunopositivity was highest in ITCL, intermediate in IEL+CE, and lower in IEL-CE. A clonal TCR gene rearrangement was detected in 1/19 IEL-CE cases (5%), 15/54 IEL+CE (28%), and 38/58 ITCL (66%). These results indicate that the immunophenotype of canine ITCL (CD8-GRB+) is similar to that of the increased IELs in CE. The high proliferative activity and clonality of T cells in IEL+CE suggest that canine ITCL originates from these IELs, similar to human EATL.

Bronchoalveolar lavage lymphocytosis in hypersensitivity pneumonitis: a retrospective cohort analysis with elimination of incorporation bias.

BACKGROUND: Recent studies support the diagnostic role of bronchoalveolar lavage lymphocytosis (BALL) in patients with suspected hypersensitivity pneumonitis (HP). Our study aim was to determine the spectrum of BALL findings with elimination of incorporation bias in non-fibrotic and fibrotic patients and assess correlates of positive BALL cut-off and BALL association with long-term outcomes in those with fibrotic disease (f-HP). METHODS: A single-center retrospective cohort study was pursued of patients undergoing diagnostic bronchoscopy for interstitial lung disease. Strict study enrollment was based on recent ATS/JRS/ALAT diagnostic guidance meeting 'moderate' or higher diagnostic confidence. BALL findings were assessed in both fibrotic and non-fibrotic HP patients with regression and survival analysis pursued for correlates of positive BALL cut-off and long-term outcome. RESULTS: A total of 148 patients (88 fibrotic and 60 non-fibrotic) meeting moderate or higher diagnostic confidence were included. Median BALL in f-HP was 15% compared to 19% in non-fibrotic patients, with only 28% of f-HP meeting diagnostic cut-off (≥ 30%) compared to 41% of non-fibrotic. For f-HP, centrilobular nodules on computed tomography was positively correlated with a diagnostic BALL (OR 4.07; p = 0.018) while honeycombing was negatively correlated (OR 6.9 × e-8; p = 0.001). Higher BALL was also associated with lower all-cause mortality (HR 0.98; p = 0.015). CONCLUSION: With elimination of incorporation bias, most patients with well-described HP did not meet diagnostic BALL thresholds. Higher BALL was associated with better long-term survival in those with fibrosis, but its diagnostic role may be more additive than characteristic or distinguishing.

Development of Monoclonal B-cell Lymphocytosis Shortly After Treatment with Nivolumab and Subsequent Progression to Chronic Lymphocytic Leukemia.

INTRODUCTION: Immune checkpoint inhibitors, such as programmed death (PD)-1 inhibitor nivolumab, are currently widely used in treatment of various malignancies. Due to their widespread application, any new potential adverse effects due to these agents necessitate careful assessment. CASE REPORT: We report a case of an 81-year-old man with recurrent high-risk malignant melanoma who underwent a 12-month adjuvant treatment with nivolumab. Shortly after the course of nivolumab, he developed monoclonal B-cell lymphocytosis (MBL) which subsequently progressed to chronic lymphocytic leukemia (CLL). MANAGEMENT AND OUTCOME: The patient is currently doing clinically well in Rai stage 0. Malignant melanoma remains in remission. CONCLUSION: Considering the pathophysiologic plausibility of nivolumab inducing B-cell dysregulation via PD-1 inhibition, we suggest further studies on potential association between nivolumab and B-cell malignancies.

From the archives of MD Anderson Cancer Center: Untreated leukemic non-nodal mantle cell lymphoma with relapse as pleomorphic variant mantle cell lymphoma 21 years later.

Leukemic, non-nodal mantle cell lymphoma (MCL) is a distinct, rare, indolent variant of mantle cell lymphoma, but can relapse aggressively. It can present with lymphocytosis with chronic lymphocytic leukemia (CLL)-like morphologic and immunophenotypic features as was initially considered in the index case. However, at time of splenectomy, two years later cyclin D1 overexpression was shown and the disease was realized to be leukemic non-nodal MCL. The patient was followed for 21 years, without therapy, before he developed clinically aggressive MCL with lymphadenopathy. Lymph node biopsy showed MCL, pleomorphic variant. We review the literature and discuss the features of leukemic non-nodal MCL as well as the potential pitfalls in diagnosis. Furthermore, we are not aware of another cases reported with a 21 year interval from initial diagnosis of leukemic non-nodal MCL to aggressive MCL.

A case report of a transient splenial lesion related to HaNDL syndrome.

BACKGROUND: Transient lesions in the splenium of the corpus callosum have been identified in many clinical cases, and often correspond to a metabolic insult to the brain. The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome) is a rare but under-recognised headache syndrome. CASE: A 47-year-old man presented to our hospital with a 2-week history of intermittent headache, and acute right sided hemisensory deficit. A CSF lymphocytosis was found and a diagnosis of HaNDL was made. A lesion in the splenium of the corpus callosum was identified on MRI. CSF lymphocytosis and the splenial lesion resolved on follow up 4 weeks later. CONCLUSION: These two entities are uncommon but increasingly recognised. The co-incidence in this patient raises the possibility of similar underlying pathological mechanisms, including vasomotor changes in blood vessels, cortical spreading depression and glutamate excitotoxicity leading to intra-myelinic oedema. Awareness of these entities will allow prompt diagnosis, preventing unnecessary tests and treatment, and allow appropriate patient management.

Parvovirus B19 Myocarditis: Looking Beyond the Heart.

Human parvovirus B19 represents the most common etiology of myocarditis in the pediatric population. Although it usually causes a benign exanthematic viral infection, parvovirus B19 may also present as disseminated disease with tropism for the myocardium, causing heart failure with high mortality. We present the case of a 2-year-old patient with fulminating acute myocarditis in whom the histological, immunophenotypic, and microbiological findings in necropsy showed multiorgan involvement caused by parvovirus B19. The autopsy revealed changes due to infection with parvovirus B19 as well as hypoxic-ischemic and secondary autoimmune changes. Medullary aplasia was observed, transmural lymphocyte myocarditis, lymphocytosis in the dermis with endothelial cells positive for parvovirus B19 in immunohistochemistry, cholestatic hepatitis due to ischemia and autoimmune hepatitis, lymphadenitis, and signs of hemophagocytosis. We also found hypoxic-ischemic encephalopathy.

Composite monoclonal B-cell lymphocytosis and MYD88 L265P-positive lymphoplasmacytic lymphoma in a patient with IgM light chain amyloidosis: Case report.

Monoclonal B-cell lymphocytosis (MBL) is an early or precursor asymptomatic proliferation of chronic lymphocytic lymphoma (CLL)-like B-cells. Lymphoplasmacytic lymphoma (LPL), often clinically associated with Waldenström macroglobulinemia, is a B-cell neoplasm characterized by frequent MYD88 L265P mutation. Here, we report a rare composite MBL and LPL in a patient with IgM light chain (AL) amyloidosis. A 74-year-old male with a known IgM monoclonal protein developed proteinuria. No lymphocytosis was detected. Renal biopsy showed deposition of AL λ amyloid in the glomeruli and vessels. Subsequent bone marrow biopsy revealed nodular atypical CLL-like small B-cell proliferation and scattered peripheral LPL. Immunohistochemistry and/or flow cytometry revealed that the atypical CLL-like population expressed CD19, CD20, CD5, weak CD23, LEF-1 and diminished surface Igκ. The LPL was positive for CD19, CD20 and surface Igλ. Using laser-capture microdissection and allele-specific polymerase chain reaction, we confirmed that MYD88 L265P was detectable in the LPL but not in the atypical CLL-like population. Thus, we demonstrated that these two populations were clonally independent, and made the diagnosis of composite MBL and LPL. An integrated clinical, pathological, immunophenotypic and genetic assessment is essential in such complicated cases, and especially 'clone-specific' MYD88 genotyping may facilitate the differential diagnoses of low-grade B-cell lymphomas.

Hypersensitivity pneumonitis: clinical, radiological and pathological profile of 103 patients from North India.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease, commonly occurring due to exposure to various inciting agent related to occupation. Few studies have shown that it can also occur without any occupation exposure. In this study we are presenting clinical, radiological and bronchoscopic finding of 103 HP patients. We retrospective analysis of 5½ years HP patient's data from a chest institute of India. The diagnosis of HP was considered with following criteria: i) known exposure to an inciting antigen; ii) presence of respiratory symptoms; iii) radiologic evidence of diffuse lung disease; iv) no other identifiable cause; v) lung biopsy specimen that demonstrated features of HP; and vi) bronchoalveolar lavage lymphocytosis (≥30%). The mean ±SD age was 47±12.8 years; 67% were female. The common symptoms were cough (97%) and dyspnea (91%). History of exposure to inciting agent was present in 61% with pigeon exposure being the most common (56%). Majority of patients (86%) were having chronic symptoms for >6 months. On 6MWT oxygen desaturation >4% was seen in 57% patients. Centrilobular nodules (61%) and ground glass opacity (47.5%) were common finding on HRCT chest. Bronchoalveolar lavage (BAL) lymphocytosis >30% was present in 48.5% and histopathological diagnosis HP on transbronchial lung biopsy (TBLB) and/or endobronchial lung biopsy (EBLB) was in 50% patients. HP is exposure related environmental disease, as it can occur without any occupational history. Bronchoscopy with BAL and lung biopsy should do in all suspected cases to confirm diagnosis in our country as it is less invasive, day care procedure with less complication.

Clinical, endoscopic, and histologic characteristics of lymphocytic esophagitis: a systematic review.

OBJECTIVE: Lymphocytic esophagitis (LyE) is a novel, yet poorly described, clinicopathologic entity. The aim of this systematic review was to characterize the demographic, clinical, endoscopic, and histologic features of LyE in observational studies of adult and pediatric patients. DESIGN: We searched the Embase, MEDLINE, and SCOPUS databases for relevant studies in 2018. Two authors reviewed and extracted data from studies that met the inclusion and exclusion criteria. RESULTS: We identified 20 studies for analysis of demographic, clinical, and endoscopic features of LyE. The mean age ranged from 9 to 67 years. When pooled, there were 231 (52.7%) patients with LyE that were female. The most common presenting symptom was dysphagia reported in 191 (48.8%) patients. On endoscopy, most patients with LyE tended to have abnormal findings (69.0%), which included erosive esophagitis, multiple esophageal rings, linear furrows, and narrow-caliber esophagus. In the 31 studies used to assess the histologic definition, the cut-off number of intraepithelial lymphocytes (IELs) was reported in 16 (51.6%) studies, peripapillary IEL specification in 18 (58.1%) studies, and presence of spongiosis in 6 (19.4%) studies. CONCLUSION: We identified a spectrum of demographic, clinical, and endoscopic findings characteristic of patients with LyE. A consensus on the diagnostic criteria of LyE is required.

Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations.

Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we performed whole-genome sequencing in 11 individuals with monoclonal B- cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

Low-count monoclonal B-cell lymphocytosis persists after seven years of follow up and is associated with a poorer outcome.

Low-count monoclonal B-cell lymphocytosis is defined by the presence of very low numbers of circulating clonal B cells, usually phenotypically similar to chronic lymphocytic leukemia cells, whose biological and clinical significance remains elusive. Herein, we re-evaluated 65/91 low-count monoclonal B-cell lymphocytosis cases (54 chronic lymphocytic leukemia-like and 11 non-chronic lymphocytic leukemia-like) followed-up for a median of seven years, using high-sensitivity flow cytometry and interphase fluorescence in situ hybridization. Overall, the clone size significantly increased in 69% of low-count monoclonal B-cell lymphocytosis cases, but only one subject progressed to high-count monoclonal B-cell lymphocytosis. In parallel, the frequency of cytogenetic alterations increased over time (32% vs 61% of cases, respectively). The absolute number of the major T-cell and natural killer cell populations also increased, but only among chronic lymphocytic leukemia-like cases with increased clone size vs age- and sex-matched controls. Although progression to chronic lymphocytic leukemia was not observed, the overall survival of low-count monoclonal B-cell lymphocytosis individuals was significantly reduced vs non-monoclonal B-cell lymphocytosis controls (P=0.03) plus the general population from the same region (P≤0.001), particularly among females (P=0.01); infection and cancer were the main causes of death in low-count monoclonal B-cell lymphocytosis. In summary, despite the fact that mid-term progression from low-count monoclonal B-cell lymphocytosis to high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia appears to be unlikely, these clones persist at increased numbers, usually carrying more genetic alterations, and might thus be a marker of an impaired immune system indirectly associated with a poorer outcome, particularly among females.

Lymphoma-like monoclonal B cell lymphocytosis in a patient population: biology, natural evolution, and differences from CLL-like clones.

High-count monoclonal B cell lymphocytosis (MBL) with a chronic lymphocytic leukemia (CLL) phenotype is a well-known entity, featuring 1-4% annual risk of progression towards CLL requiring treatment. Lymphoma-like MBL (L-MBL), on the other hand, remains poorly defined and data regarding outcome are lacking. We retrospectively evaluated 33 L-MBL cases within our hospital population and compared them to 95 subjects with CLL-like MBL (C-MBL). Diagnoses of L-MBL were based on asymptomatic B cell clones with Matutes score < 3, B cells < 5.0 × 103/µl, and negative computerized tomography scans. We found that median B cell counts were considerably lower compared to C-MBL (0.6 vs 2.3 × 103/µl) and remained stable over time. Based on immunophenotyping and immunogenetic profiling, most L-MBL clones did not correspond to known lymphoma entities. A strikingly high occurrence of paraproteinemia (48%), hypogammaglobulinemia (45%), and biclonality (21%) was seen; these incidences being significantly higher than in C-MBL (17, 21, and 5%, respectively). Unrelated monoclonal gammopathy of undetermined significance was a frequent feature, as the light chain type of 5/12 paraproteins detected was different from the clonal surface immunoglobulin. After 46-month median follow-up, 2/24 patients (8%) had progressed towards indolent lymphoma requiring no treatment. In contrast, 41% of C-MBL cases evolved to CLL and 17% required treatment. We conclude that clinical L-MBL is characterized by pronounced immune dysregulation and very slow or absent progression, clearly separating it from its CLL-like counterpart.

Intrinsic renal cells induce lymphocytosis of Th22 cells from IgA nephropathy patients through B7-CTLA-4 and CCL-CCR pathways.

IgA nephropathy (IgAN), the most common glomerulonephritis, has an unclear pathogenesis. The role of Th22 cells, which are intimately related to proteinuria and progression in IgAN, in mediating infection-related IgAN is unclear. This study aimed to characterize the association between intrinsic renal cells (tubular epithelial cells and mesangial cells) and Th22 cells in immune regulation of infection-related IgAN and to elucidate the impact of Th22 lymphocytosis; the proinflammatory cytokines IL-1, IL-6, and TNF-α; and CCL chemokines on kidney fibrosis. Hemolytic streptococcus infection induced an increase in IL-1, IL-6, and TNF-α, resulting in Th22 cell differentiation from T lymphocytes obtained from patients with IgAN, and the CCL20-CCR6, CCL22-CCR4, and/or CCL27-CCR10 axes facilitated Th22 cell chemotaxis. The increased amount of Th22 cells caused an increase in TGF-ß1 levels, and anti-CD80, anti-CD86, and CTLA-4Ig treatment reduced TGF-ß1 levels by inhibiting Th22 lymphocytosis and secretion of cytokines and chemokines, thus potentially relieving kidney fibrosis. Our data suggest that Th22 cells might be recruited into the kidneys via the CCL20-CCR6, CCL22-CCR4, and/or CCL27-CCR10 axes by mesangial cells and tubular epithelial cells in infection-related IgAN. Th22 cell overrepresentation was attributed to stimulation of the B7-CTLA-4Ig antigen-presenting pathway and IL-1, IL-6, and TNF-α.