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Immune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute myeloid leukemia, myelodysplastic syndromes (MDS), chronic myeloproliferative neoplasms, and bone marrow failure (BMF) syndromes. Autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance and may result, along with contributing environmental and genetic factors, in an increased incidence of both tumors and infections. The latter may fuel both autoimmunity and immune activation, triggering a vicious circle among infections, tumors and autoimmune phenomena. Additionally, alterations of the microbiota and of mesenchymal stem cells (MSCs) pinpoint to the importance of a permissive or hostile microenvironment for tumor growth. Finally, several therapies of myeloid neoplasms are aimed at increasing host immunity against the tumor, but at the price of increased autoimmune phenomena. In this review we will examine the epidemiological association of myeloid neoplasms with autoimmune diseases and immunodeficiencies, and the pivotal role of autoimmunity in the pathogenesis of MDS and BMF syndromes, including the paroxysmal nocturnal hemoglobinuria conundrum. Furthermore, we will briefly examine autoimmune complications following therapy of myeloid neoplasms, as well as the role of MSCs and microbiota in these settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Barcellini and Fattizzo.)

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

Graft-versus-host disease (GVHD) constitutes the most frequent complications after the allogeneic hematopoietic stem cell transplantation for a variety of hematological malignancies. In the present study, we explored the prophylactic potential of adipose tissue-derived mesenchymal stem cells (AD-MSCs) in controlling GVHD in murine models with a special focus on bone marrow aplasia related with acute GVHD. The CB6F1 mice were induced GVHD by the injection intravenously of C57BL/6 (B6-Ly-5.1) splenocytes without conditioning irradiation or chemotherapy. AD-MSCs from C3H mice were injected intravenously via tail veins. GVHD was assessed using flowcytometry analysis of peripheral blood cells and histopathologic analysis of target organs. Histopathological analyses revealed that AD-MSCs markedly suppressed the infiltration of lymphocytes into liver as well as the aplasia in bone marrow. This study is the first to clarify the effectiveness of AD-MSCs against bone marrow aplasia in GVHD, supporting a rationale of AD-MSCs for ameliorating bone marrow suppression and infectivity after allo-HSCT in human clinics., (Copyright © 2019. Published by Elsevier B.V.)

Shwachman-Diamond syndrome (SDS) is one of the more common inherited bone marrow failure syndromes, characterized by neutropenia, occasional thrombocytopenia, and anemia. Bone marrow evaluation reveals an increased number of monocytes and mature B cells along with decreased granulocytes. However, little is known about the subpopulations of peripheral blood cells, and few previous publications have been based on a small number of patients. Here, we report a comprehensive immunophenotypic analysis from a cohort of 37 SDS patients who display impairment mostly in the myeloid compartment with a deficiency also in the number of B cells and CD4/CD8 double-negative T cells., (© 2019 Wiley Periodicals, Inc.)

This study investigated the combination effects of the Acanthopanax senticosus - Ligustrum lucidum (AS-LL) herb pair on bone marrow suppression caused by chemotherapy. A bone marrow suppression model was established by intraperitoneal injection (i.p.) of cyclophosphamide (CTX, 100 mg/kg). The changes in chemical composition between the AS-LL decocted together and single were analyzed, and their effects on the bone marrow nucleated cells, peripheral blood, thymus and spleen indices, in vitro hematopoietic cell culture, ELISA and cell cycle were detected. The results showed that the contents of the main active components, such as salidroside, isofraxidin and specnuezhenide in the sample of AS-LL decocted together, increased significantly compared to singles. Moreover, AS-LL decocted together exhibited a significantly better therapeutic effect on myelosuppression induced by CTX than AS and LL alone. AS-LL decocted together significantly increased the number of bone marrow nucleated cells and displayed a good regulatory effect on peripheral blood (p < 0.01), while significantly increased the thymus index (p < 0.01) and decreased the spleen index (p < 0.01). AS-LL significantly promoted the formation of cell colonies (p < 0.05), the proliferation and differentiation of hematopoietic progenitor cells, and played a positive regulatory role in hematopoietic factors. AS-LL also reduced the proportion of G0/G1 cells, increased the ratio of S and G2/M cells, and increased the cell proliferation index (PI). All these results implied that AS-LL decocted together might be a promising food additives and therapeutic agent for myelosuppression induced by chemotherapy., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α -/- donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR -/- recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α -/- recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α -/- recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR -/- donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α-producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.

Background: Indolent T-cell proliferative disorder of the GIT is a rare and provisional entity in the revised WHO 2016 classification. The patients usually have prolonged survival with persistent disease even without any treatment., Case Presentation: The 46 years old male patient has been followed up for more than 6 years without chemotherapy. Repeated gastrointestinal biopsies showed expansion of the lamina propria extending to the submucosa by small to medium sized lymphocytes with minimal cytologic atypia. The lymphoid cells were positive for CD3, CD43, TIA-1, CD2, CD7 and the B-cell marker CD20; but negative for CD4, CD8, PAX5, CD56, cyclinD1, granzyme (GraB) and Epstein Barr virus-encoded RNA (EBER). Ki-67(MIB1) index was less than 10%. Molecular tests demonstrated a clonal rearrangement for T-cell receptor γ (TCR γ) gene but immunoglobulin chain (IgH, IgK, IgL) gene remained germline. Recognition of possible aberrant CD20 expression in indolent T-cell LPD is important to avoid potential diagnostic pitfall and improper treatment., Conclusions: We present an unusual case of indolent T-cell lymphoproliferative disorder with aberrant CD20 expression, Recognition of this unusual immunophenotype of indolent T-cell LPD of GI helps to eschew misdiagnosis of B-cell and other high grade lymphomas and inappropriate aggressive treatment.

Rheumatoid arthritis is an auto-immune disease of the synovial joints, hallmarked by chronic inflammation and subsequent progressive tissue destruction. TYRO3, AXL and MER (gene name Mertk) (TAM) receptors are part of a negative feedback signaling system in the immune reaction and mediate efferocytosis thereby tempering the inflammatory process. We have shown that Axl-/- and Mertk-/- mice develop more severe arthritis whereas activating these receptors by overexpressing their ligands Pros1 and Gas6 ameliorates arthritis. Mice genetically ablated for the three genes of the TAM receptor family Tyro3/Axl/Mertk (TAM triple knock-out or TKO) have been described to spontaneously develop macroscopic signs of arthritis. In this study we aimed to analyze arthritis development in TAM TKO mice histologically to determine the extent and sequence of pathological changes in the joint. Ankle joints of three different age groups, adolescence (14 weeks), mature adult (34 weeks) and middle-age (52 weeks), of TAM TKO or wild-type mice were examined macroscopically, histologically and immunohistochemically. Surprisingly, until the age of 52 weeks, none of the mice examined developed spontaneous macroscopic signs of arthritis. There was no synovial inflammation nor any signs of damage to the cartilage or bone. However, bone marrow edema was observed in TAM TKO mice in the two latter age groups. The infiltrate in the bone marrow was characterized by both myeloid cells and lymphocytes. This study showed that TAM TKO mice developed a pre-stage (pre-clinical phase) of arthritis marked by bone marrow edema., Competing Interests: The authors have declared that no competing interests exist.

Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific manner. Although primary MDS emerges without known predisposing cause and is associated with advanced age, secondary MDS may develop in younger patients with bone marrow failure syndromes or after exposure to chemotherapy, respectively. This article discusses recent advances in the understanding of context-dependent clonal hematopoiesis in MDS with focus on clonal evolution in inherited and acquired bone marrow failure syndromes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mast cell disorders comprise a heterogeneous group of rare diseases, the diagnosis of which still remains a challenge. Bone marrow analysis constitutes the most appropriate site for screening systemic involvement in mastocytosis. Morphologic, immunohistochemical, flow cytometric immunophenotyping, and molecular studies should be routinely performed for diagnostic/prognostic purposes in experienced reference centers during the diagnostic workup in suspected systemic mastocytosis. The authors review the most relevant characteristics of bone marrow expression of mast cell disorders as well as the different methodological approaches to be applied to perform an objective and reproducible diagnosis and classification of mastocytosis and other mast cell disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced-intensity conditioning (RIC) instead of myeloablative conditioning (MAC); however, the biology underlying this treatment remains incompletely understood., Methods: We investigated a murine model of major histocompatibility complex-matched multiple minor histocompatibility antigen-mismatched alloHCT using bone marrow (BM) cells and splenocytes from B6 (H-2) donor mice transplanted into BALB.B (H-2) recipients after RIC with fludarabine of 100 mg/kg per day for 5 days, cyclophosphamide of 60 mg/kg per day for 2 days, and total body irradiation (TBI)., Results: The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice that underwent RIC had a reduced incidence and delayed onset of graft-versus-host disease (GVHD) and significantly prolonged survival compared with MAC-transplanted recipients (TBI of 850 cGy plus cyclophosphamide of 60 mg/kg per day for 2 days). Compared with syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, have anemia, reduced BM cellularity, and showed profound reduction in BM B cell lymphopoiesis associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8 effector T cells in RIC mice and elevated blood and BM plasma levels of T helper1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice., Conclusions: We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse major histocompatibility complex-matched alloHCT model by a process that seems to be driven by CD8 effector T cells.

Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. Most aplastic anemia patients respond to immunosuppressive therapy, usually with anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term administration of cyclosporine to maintain blood counts. In this study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. Rapamycin effectively reduced Th1 inflammatory cytokines interferon-γ and tumor necrosis factor-α, increased the Th2 cytokine interleukin-10, stimulated expansion of functional regulatory T cells, eliminated effector CD8 + T cells (notably T cells specific to target cells bearing minor histocompatibility antigen H60), and preserved hematopoietic stem and progenitor cells. Rapamycin, but not cyclosporine, reduced the proportion of memory and effector T cells and maintained a pool of naïve T cells. Cyclosporine increased cytoplasmic nuclear factor of activated T-cells-1 following T-cell receptor stimulation, whereas rapamycin suppressed phosphorylation of two key signaling molecules in the mammalian target of rapamycin pathway, S6 kinase and protein kinase B. In summary, rapamycin was an effective therapy in mouse models of immune-mediated bone marrow failure, acting through different mechanisms to cyclosporine. Its specific expansion of regulatory T cells and elimination of clonogenic CD8 + effectors support its potential clinical utility in the treatment of aplastic anemia., (Copyright© 2017 Ferrata Storti Foundation.)

Background: Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination. Its role in human immunity and hematopoiesis is poorly understood., Objectives: We sought to investigate the clinical, cellular, and molecular features in 2 siblings presenting with progressive bone marrow failure (BMF), immunodeficiency, and developmental aberrations., Methods: We performed genome-wide homozygosity mapping, whole-exome and Sanger sequencing, immunophenotyping studies, and analysis of genotoxic stress responses. p38 activation, reactive oxygen species levels, rate of apoptosis and clonogenic survival, and growth in immune and nonimmune cells were assessed. The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) was monitored., Results: We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts. Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1. MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased reactive oxygen species production, and decreased survival following UV light-induced DNA damage. Both patients were successfully treated with allogeneic HSCT with sustained reconstitution of hematopoietic defects., Conclusions: Here we show that MYSM1 deficiency is associated with developmental aberrations, progressive BMF with myelodysplastic features, and increased susceptibility to genotoxic stress. HSCT represents a curative therapy for patients with MYSM1 deficiency., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Kingella denitrificans is a non-pathogenic micro-organism present in oropharyngeal flora. This germ has been recently recognized as responsible for opportunistic invasive infections mainly affecting immunosuppressed patients. We here report the case of a child aged 3 years and 7 months followed-up since the age of one year for bone marrow failure syndrome associated with pancytopenia of undetermined origin who had bacteremia due to Kingella denitrificans, a group of difficult to culture gram-negative bacteria rarely described in the literature. Clinicians and microbiologists should suspect the presence of this germ especially in immunosuppressed patients. The use of blood culture bottle contributes in a significant way to the detection of this germ.

We report the first case of a patient with hepatitis C virus (HCV) infection and idiopathic thrombocytopenic purpura (ITP), who later developed acquired amegakaryocytic thrombocytopenia (AAMT), with autoantibodies to the thrombopoietin (TPO) receptor (c-Mpl). A 64-year-old woman, with chronic hepatitis C, developed severe thrombocytopenia and was diagnosed with ITP. She died of liver failure. Autopsy revealed cirrhosis and liver carcinoma. In the bone marrow, a marked reduction in the number of megakaryocytes was observed, while other cell lineages were preserved. Therefore, she was diagnosed with AAMT. Additionally, autoantibodies to c-Mpl were detected in her serum. Autoantibodies to c-Mpl are one of the causes of AAMT, acting through inhibition of TPO function, megakaryocytic maturation, and platelet formation. HCV infection induces several autoantibodies. HCV infection might also induce autoantibodies to c-Mpl, resulting in the development of AAMT. This mechanism may be one of the causes of thrombocytopenia in patients with HCV infection., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest.

Patients with inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia (FA), dyskeratosis congenita (DC), or Diamond Blackfan anemia (DBA), can have hematologic manifestations cured through hematopoietic cell transplantation (HCT). Subsequent late effects seen in these patients arise from a combination of the underlying disease, the pre-HCT therapy, and the HCT process. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium on late effects screening and recommendations following allogeneic hematopoietic cell transplantation for immune deficiency and nonmalignant hematologic diseases held in Minneapolis, Minnesota in May 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. This multidisciplinary group of experts in rare diseases and transplantation late effects has already published on the state of the science in this area, along with discussion of an agenda for future research. This companion article outlines consensus disease-specific long-term follow-up screening guidelines for patients with IMBFS., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.)

The aim of this study is to investigate the relationship between the epidemiological and clinical profiles of patients before and after hematopoietic stem cell transplantation (HSCT) and the need for endodontic treatment. The subjects included 188 individuals enrolled in the dental care program for transplanted patients of the School of Dentistry, Federal University of Minas Gerais (Faculdade de Odontologia da Universidade Federal de Minas Gerais, FO-UFMG) from March 2011 through March 2016. The patients were subjected to an HSCT conditioning dental regimen based on a thorough clinical and radiographic evaluation. Intraoral periapical and bite-wing X-rays were obtained, and after evaluation, specific dental treatment was planned and performed. The following demographic and clinical data were collected from the patients' medical records: age, gender, transplantation stage, primary disease, transplant type, medication used, complete blood count at the time of visit, and need for endodontic treatment. The Kolmogorov-Smirnov and the chi-square tests were used. Leukemia (31.3%) and multiple myeloma (17.9%) were the most prevalent primary diseases. Most patients were subjected to allogeneic-related transplantation (83.6%). Most patients exhibited platelet counts and hemoglobin concentrations below the reference values in the pre-transplantation stage, while the neutrophil and platelet counts and the hemoglobin levels were within the reference ranges in the post-transplantation stage. The proportions of individuals requiring endodontic treatment were similar between the pre- and post-transplantation groups: 24.3% and 24.7%, respectively. The systemic conditions of the patients referred for dental treatment were compromised.

Introduction: This review examines the several lines of evidence that support the relationship between myelodysplasia and autoimmunity, i.e. their epidemiologic association, the existence of common immune-mediated physiopathologic mechanisms, and the response to similar immunosuppressive therapies. The same relationship is reviewed here considering idiopathic cytopenia of uncertain significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), two recently recognized provisional conditions characterized by isolated/unexplained cytopenia and/or dysplasia in <10% bone marrow cells. Areas covered: The review focuses on alterations of cytokine profiles, telomere/telomerase and toll-like receptors, and on increased myelosuppressive mediators and apoptotic markers in both myelodysplasia and autoimmunity. In addition, the presence of an autoimmune reaction directed against marrow precursors is described in refractory/relapsing autoimmune cytopenias (autoimmune hemolytic anemia, immune thrombocytopenia, chronic idiopathic neutropenia), possibly contributing to their evolution to ICUS/IDUS/bone marrow failure syndromes. Expert commentary: The increasing availability of omics methods has fuelled the discussion on the role of somatic mutations in the pathogenesis of IDUS/ICUS, clonal hematopoiesis of indeterminate potential, and clonal cytopenias of undetermined significance, and in their possible evolution. Even more attracting is the involvement of the genetic background/accumulating somatic mutations in cytopenias with autoimmune alterations.

Background: Primary immunoglobulin light chain amyloidosis (AL amyloidosis) is a plasma cell disorder which mainly affects heart, kidneys, liver, and peripheral nervous system. Cases of atypical AL amyloidosis presented as spontaneous vertebral compression fractures have been rarely reported, and data about the management and clinical outcomes of the patients are scarce., Methods: Herein, we present 3 new cases of AL amyloidosis with spontaneous vertebral compression fracture and review 13 cases retrieved from the literature., Results: Moreover, we observed overrepresentations of liver involvement and bone marrow involvement in AL amyloidosis with spontaneous vertebral compression fracture., Conclusion: We believe that better awareness of the rare clinical presentation as spontaneous vertebral compression fracture of AL amyloidosis can facilitate earlier diagnosis and earlier treatment., Competing Interests: The authors have no conflicts of interest to disclose.

Chemotherapy damages immune system and has a lot of side effects. In this study, we investigate the function of Shenfu injection to reduce these unfavorable effects induced by chemotherapy on mice bearing Lewis lung sarcoma. Mice inoculated with Lewis lung sarcoma cells were divided into five groups: Lewis lung sarcoma control group, cyclophosphamide (CTX) group, and Shenfu injection (high, moderate, and low dose) + CTX group. After a 14-day treatment, the counting of peripheral blood cells, CD3+, CD4+, and CD8+ T lymphocytes were done, immunoglobulin (Ig) was measured, coefficients of spleen and thymus were calculated, and spleen T cell proliferation was evaluated in vitro. The CD4+/CD8+ and CD3+ T cells in high- and moderate-dose Shenfu groups were more than the CTX group (p < 0.05); spleen T cell proliferation of mice in high-dose Shenfu + CTX group is more prominent than the CTX group (p < 0.05); coefficients of spleen and thymus, WBC, and platelet (PLT) counting of mice in the CTX group were lower than control and high and moderate dose Shenfu + CTX groups. The level of serous IgG and IgM of all test groups shows no significant difference. Shenfu injection can improve cellular immune function and reduce myolosuppression of mice delivered with chemotherapy.

Background: Cellular engraftment after allogeneic hematopoietic progenitor cell transplantation (HPCT) can be affected by pre-HPCT antibodies against donor human leukocyte antigen (HLA; donor-specific antibodies [DSAs]), which are commonly acquired by either pregnancy or transfusion. Issues regarding high assay sensitivity and variable interpretation limit routine screening for DSAs. Platelet (PLT) transfusion refractoriness (PTR) is relatively common in patients with hematologic malignancies, and anti-HLA alloantibodies can be identified in up to 20% of cases. For patients with PTR undergoing subsequent allogeneic HPCT, however, the effect if any on subsequent PLT nonengraftment is unknown., Study Design and Methods: We conducted a retrospective study of 480 adults who underwent T-replete HPCT for hematologic malignancy and compared the posttransplantation clinical outcomes between patients who were PTR before HPCT and those who were not., Results: Multivariate analysis demonstrated that PTR was not directly associated with PLT nonengraftment or graft failure, but did predict for early intensive care unit admission, which was the only variable associated with these outcomes (p < 0.0001)., Conclusion: Our findings suggest that PTR before HPCT identifies patients at higher risk of early clinical rather than immunologic complications., (© 2015 AABB.)

Immune function abnormalities have been reported in patients with Fanconi anemia (FA), dyskeratosis congenita (DC) and, rarely, in Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), but large systematic studies are lacking. We assessed immunological parameters in 118 patients with these syndromes and 202 unaffected relatives. We compared the results in patients with reference values, and with values in relatives after adjusting for age, sex, corticosteroid treatment, and severe bone marrow failure (BMF). Adult patients (≥18 years) with FA had significantly lower immunoglobulins (IgG, IgA and IgM), total lymphocytes, and CD4 T cells than reference values or adult relatives (P < 0.001); children with FA had normal values. Both children and adults with FA had lower B- and NK cells (P < 0.01) than relatives or reference values. Patients with DC had essentially normal immunoglobulins but lower total lymphocytes than reference values or relatives, and lower T-, B-, and NK-cells; these changes were more marked in children than adults (P < 0.01). Most patients with DBA and SDS had normal immunoglobulins and lymphocytes. Lymphoproliferative responses, serum cytokine levels, including tumor necrosis factor-α and interferon-γ, and cytokine levels in supernatants from phytohemagglutinin-stimulated cultures were similar across patient groups and relatives. Only patients with severe BMF, particularly those with FA and DC, had higher serum G-CSF and Flt3-ligand and lower RANTES levels compared with all other groups or relatives (P < 0.05). Overall, immune function abnormalities were seen mainly in adult patients with FA, which likely reflects their disease-related progression, and in children with DC, which may be a feature of early-onset severe disease phenotype., (© 2015 Wiley Periodicals, Inc.)

Objective: To determine the prevalence, on magnetic resonance imaging (MRI), of bone marrow edema lesions in symptomatic axial psoriatic arthritis (PsA), and to compare this prevalence with that in nonradiographic axial spondyloarthritis (SpA) and ankylosing spondylitis (AS) and its relationship to HLA-B27 status., Methods: We performed a cross-sectional audit of MRI scans of lumbar spine (L-spine) and sacroiliac (SI) joints. Using the semiquantitative Leeds Scoring System in which bone marrow edema is graded from 0 to 3 according to severity of the lesions, MRI scans were scored independently by 2 expert readers who were blinded to the clinical characteristics of the patients. Concordant data from the 2 readers were used to report on definite lesions., Results: MRIs from 76 patients with comparable age ranges were categorized into 3 groups: those from PsA patients, those from patients with nonradiographic axial SpA, and those from AS patients. HLA-B27 positivity was similar in PsA patients (10 of 33) and patients with nonradiographic axial SpA (10 of 24) and higher in AS patients (18 of 19). Total MRI scores (L-spine plus SI joints) were higher in AS patients than in PsA patients (P = 0.025) or in patients with nonradiographic axial SpA (P = 0.007). A relationship was seen between the severity and extent of disease and HLA-B27 positivity in PsA patients, which was comparable to that in AS patients. HLA-B27-negative PsA patients had lower MRI scores than HLA-B27-positive PsA patients (P = 0.03) and AS patients (P = 0.006), whereas scores were similar in HLA-B27-positive PsA patients and AS patients. Similarly, MRI scores of HLA-B27-negative patients with nonradiographic axial SpA were lower than those of AS patients (P = 0.01)., Conclusion: HLA-B27 positivity defines a group of patients with more severe axial bone marrow edema that is likely related to the classic AS phenotype. Clinically, HLA-B27-negative PsA is more likely to be reported as a "negative" MRI examination result., (Copyright © 2013 by the American College of Rheumatology.)

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive, susceptibility to infections and short stature. A persistent or intermittent neutropenia occurs in 88-100% of patients. Bone marrow biopsy usually reveals a hypoplastic specimen with varying degrees of hypoplasia and fat infiltration. Some patients may develop myeloblastic syndrome and acute myeloblastic leukemia. The genetic defect in SDS has been identified in 2002. The osteoporosis is increased in patients with SDS, and also, bone malformations are included among the primary characteristics of the syndrome. The severity and location change with age and sexes. The typical characteristics include the following: secondary ossification centers delayed appearance, metaphysis enlargement and irregularity (very common in childhood, particularly in coastal and femur), growth cartilage progressive thinning and irregularity (possibly asymmetric growth), generalized osteopenia with cortical thinning. We describe a clinical case regarding an SDS patient with severe bone abnormalities and treated surgically for corrective osteotomy. The persistent or intermittent neutropenia that characterized this disease and the consequent risk of infection is a contraindication for short stature correction and limbs lengthening.

Ethnopharmacological Relevance: Barleria prionitis Linn. (Family: Acanthaceae), one of the important Ayurvedic medicinal plant in India, has long been used to treat variety of ailments including swellings, gout, arthritic and rheumatic disorders, nervine and skin diseases, and also acts as immunorestorative., Aim of the Study: The present study was aimed to explore in vitro and in vivo immunomodulatory activities of the iridoids fraction i.e. n-butanol fraction of methanol extract from Barleria prionitis aerial parts (IFBp)., Materials and Methods: IFBp was studied for in vitro [nitroblue tetrazolium (NBT) test and neutrophils candidacidal assay] and in vivo immunomodulatory activity on cellular and humoral immune responses to the antigenic challenge by sheep red blood cells (SRBCs) and by neutrophil adhesion test, phagocytic activity and cyclophosphamide-induced myelosuppression. The study comprised the preliminary phytochemical screening, HPTLC standardization and maximum tolerable dose determination of IFBp., Results: IFBp (50, 100 and 200μg/ml) significantly (P≤0.01) increased the intracellular killing activity of stimulated neutrophils assayed by in vitro NBT reduction test and neutrophils candidacidal assay. Pretreatment of IFBp (100 and 200mg/kg; p.o.) evoked a significant increase in percent neutrophils and neutrophils adhesion to nylon fibres. Oral administration of IFBp augmented the humoral immune response to SRBCs, evidenced by increase in antibody titres and dose dependently potentiated the delayed-type hypersensitivity reaction induced by SRBCs in mice. IFBp potentiated significantly (P≤0.01) the macrophage phagocytic activity and ameliorated the red blood cells, total white blood cells and platelets count and haemoglobin concentration, and also restored the myelosuppressive effects induced by cyclophosphamide. The content (% w/w; mean±SD, n=3) of main iridoids i.e. shanzhiside methyl ester and barlerin was found to be 21.55±2.40 and 10.03±1.69 in IFBp of BP, respectively., Conclusion: The present investigation reveals that IFBp is a potent immunostimulant, stimulating both the specific and non-specific immune mechanisms., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The detonation of a nuclear weapon or a nuclear accident represent possible events with significant exposure to mixed neutron/γ-radiation fields. Although radiation countermeasures generally have been studied in subjects exposed to pure photons (γ or X rays), the mechanisms of injury of these low linear energy transfer (LET) radiations are different from those of high-LET radiation such as neutrons, and these differences may affect countermeasure efficacy. We compared 30-day survival in mice after varying doses of pure γ and mixed neutron/γ (mixed field) radiation (MF, Dn/Dt = 0.65), and also examined peripheral blood cells, bone marrow cell reconstitution, and cytokine expression. Mixed-field-irradiated mice displayed prolonged defects in T-cell populations compared to mice irradiated with pure γ photons. In mouse survival assays, the growth factor granulocyte colony-stimulating factor (G-CSF) was effective as a (post-irradiation) mitigator against both γ-photons and mixed-field radiation, while the thrombopoietin (TPO) mimetic ALXN4100TPO was effective only against γ irradiation. The results indicate that radiation countermeasures should be tested against radiation qualities appropriate for specific scenarios before inclusion in response plans.

For many nonmalignant hematological disorders, HLA-matched bone marrow transplantation (BMT) is curative. However, due to lack of neoplasia, the toxicity of stringent conditioning regimens is difficult to justify, and reduced intensity conditioning is used. Unfortunately, current reduced intensity regimens have high rates of BMT rejection. We have recently reported in a murine model that mHAs on transfused platelet products induce subsequent BMT rejection. Most nonmalignant hematological disorders require transfusion support prior to BMT and the rate of BMT rejection in humans correlates with the number of transfusions given. Herein, we perform a mechanistic analysis of platelet transfusion-induced BMT rejection and report that unlike exposure to alloantigens during transplantation, platelet transfusion primes alloimmunity but does not stimulate full effector function. Subsequent BMT is itself an additional and distinct immunizing event, which does not induce rejection without antecedent priming from transfusion. Both CD4(+) and CD8(+) T cells are required for priming during platelet transfusion, but only CD8(+) T cells are required for BMT rejection. In neither case are antibodies required for rejection to occur., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

According to a model described by Balducci, the human myelopoietic stem cell reserve shows a shift from the reproductive to the proliferative pool corresponding to higher immunological demands resulting from the breakdown of infection defences. Every "hematopoietic stress," i.e., sepsis and/or cytoreductive chemotherapy, leads to a reduction of myelopoietic stem cells in the elderly in contrast to an increase in younger individuals. These changes are relevant starting at the age of 70 years and show a reduced compensation capacity in the aged organism. In addition, the function of the effector cells, i.e., the granulocytes and especially their phagocytic capacity, as well as the balance between stimulating and inhibiting cytokines are compromised. A significant influence on leukopenia and febrile septicemia has been shown for several comorbidities, especially chronic inflammation. The prophylactic use of myelopoietic growth factors is, therefore, recommended for the elderly when there is an expected risk for hematotoxicity grade III or IV. However, prognostic tests to predict the individual risk of hematotoxicity and septicemia are lacking.

Shwachman-Diamond syndrome is a rare clinical condition consisting of exocrine pancreatic dysfunction, various degree of pancytopenia, and metaphyseal dysplasia. The majority of Shwachman-Diamond syndrome cases result from mutations in the Shwachman-Bodian-Diamond Syndrome gene. To date, type 1 diabetes mellitus has only been reported in 4 independent cases presenting with Shwachman-Diamond syndrome, 3 of them with molecular confirmation of the diagnosis. We describe 2 unrelated patients with clinical and molecular features typical of Shwachman-Diamond syndrome and type 1 diabetes mellitus. In addition, we report the occurrence rate of type 1 diabetes mellitus in the Italian registry for Shwachman-Diamond syndrome, which is low (3.23%) but increased at least 30-fold over the type 1 diabetes mellitus occurrence rate in the general population. No evidence of a direct correlation between Shwachman-Diamond syndrome and type 1 diabetes mellitus have been reported, therefore the presence of both diseases in the same patient might be a chance association, however we suggest that the defects in immune regulation of Shwachman-Diamond syndrome might play a role in the development of type 1 diabetes mellitus., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To test the hypothesis that γ-interferon (IFN-γ) promotes major histocompatibility complex (MHC) class II expression on bone marrow (BM) cell targets that facilitate T-cell-mediated BM destruction in immune-mediated BM failure., Materials and Methods: Allogeneic lymph node (LN) cells were infused into MHC- or minor histocompatibility antigen-mismatched hosts to induce BM failure. MHC class II and Fas expression and cell apoptosis were analyzed by flow cytometry. MHC class II-Fas colocalization was detected by ImageStream Imaging Flow Cytometry and other cell-to-cell associations were visualized by confocal microscopy. T-cell-mediated BM cell apoptosis and effects of IFN-γ on MHC class II-Fas colocalization on normal BM cells were studied using cell culture in vitro followed by conventional and imaging flow cytometry., Results: BM failure animals had significantly upregulated MHC class II expression on CD4(-)CD8(-)CD11b(-)CD45R(-) residual BM cells and significantly increased MHC class II-Fas colocalization on BM CD150(+) and CD34(+) hematopoietic cells. MHC class II(+)Fas(+) BM cells were closely associated with CD4(+) T cells in the BM of affected animals, and they were significantly more responsive to T-cell-mediated cell apoptosis relative to MHC class II(-)Fas(-) BM cells. Infusion of IFN-γ-deficient LN cells into minor histocompatibility antigen-mismatched recipients resulted in no MHC class II-Fas upregulation and no clinically overt BM failure. Treatment with recombinant IFN-γ significantly increased both MHC class II-Fas coexpression and colocalization on normal BM cells., Conclusions: Elevation of the inflammatory cytokine IFN-γ-stimulated MHC class II expression and MHC class II-Fas colocalization, which may facilitate T-cell-mediated cell destruction., (Published by Elsevier Inc.)

Background: The inherited bone marrow failure syndromes (IBMFS) include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome (SDS). Previous studies reported decreased neutrophil chemotaxis in patients with SDS; there are no reports of neutrophil function in other IBMFS. In this study we examined neutrophil respiratory burst function in IBMFS patients., Procedure: Samples from 43 IBMFS patients and 61 healthy family members were collected, shipped, and analyzed within 24 hr. We also studied samples from 12 healthy control persons immediately after collection. Neutrophils were stimulated with phorbol 12-myristate acetate (PMA) and N-formyl-methyonyl-leucyl-phenylalanine (fMLP), and respiratory burst analyzed by reduction of dihydro-rhodamine and cytochrome c., Results: There was no significant difference in the degree of fMLP or PMA-driven respiratory burst activity between each of the IBMFS subgroups and their respective family members. There was also no difference in respiratory burst activity between any IBMFS, pooled group of all healthy family members and healthy controls., Conclusions: Neutrophil respiratory burst activity from IBMFS patients does not differ from that of healthy family members and controls., (Copyright © 2010 Wiley-Liss, Inc.)

The European Group for Blood and Marrow Transplantation has recently run a prospective, randomized trial comparing an early (3 months) vs a late (9 months) immunization program after allo-SCT with three doses of the conjugate 7-valent pneumococcal vaccine. This trial has shown that the response rate assessed 1 month after the third dose of conjugate vaccine was not inferior after an early vaccination vs a late vaccination. Part of the responder cohort of these patients (n=28) were chosen to assess the functionality of the anti-pneumococcal antibodies through an opsonophagocytic assay, 1 month after the third dose of conjugate vaccine. We have assessed the relationship between IgG titers measured by the pneumococcal ELISA and functional titers measured by opsonophagocytic assay of anti-pneumococcal antibodies. We found a significant correlation between titers for both assays, and conclude that the response to PCV7 after SCT induces functional antibodies.

Aim: To review the gastrointestinal mucosal histological features of biopsies from children with Shwachman-Diamond syndrome (SDS) examined at a single specialist centre., Methods: Search of a clinical database was performed to identify SDS cases and their gastrointestinal biopsies were reviewed for morphological parameters such as crypt:villous ratio, crypt hyperplasia and abnormal inflammatory infiltrates. Histological sections were also immunostained with CD4, CD20 and HLA-DR to determine the nature of the inflammatory infiltrate., Results: 15 SDS cases were included, 7 (47%) of which showed morphologically normal duodenal villous architecture, whereas 8 (53%) showed varying degrees of enteropathic histological features ranging from villous blunting to partial villous atrophy and duodenitis. 11/15 (73%) showed some degree of duodenal inflammation, including increased lamina propria density of plasma cells, macrophages and eosinophils., Conclusion: Varying degrees of duodenal inflammatory enteropathic features are present in more than 50% of symptomatic children with SDS. This suggests that, in addition to pure pancreatic exocrine failure, an enteropathic component may contribute to symptoms in some cases, and be potentially responsive to appropriate therapy.

The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet(-/-)). In comparison with normal C57BL6 (B6) control mice, T-bet(-/-) mice had normal cellular composition in lymphohematopoietic tissues, but T-bet(-/-) lymphocytes were functionally defective. Infusion of 5 x 10(6) T-bet(-/-) lymph node (LN) cells into sublethally irradiated, major histocompatibility complex-mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet(-/-) LN-cell dose to 10 to 23 x 10(6) per recipient led to only mild hematopoietic deficiency. Recipients of T-bet(-/-) LN cells had no expansion in T cells or interferon-gamma-producing T cells but showed a significant increase in Lin(-)Sca1(+)CD117(+)CD34(-) BM cells. Plasma transforming growth factor-beta and interleukin-17 concentrations were increased in T-bet(-/-) LN-cell recipients, possibly a compensatory up-regulation of the Th17 immune response. Continuous infusion of interferon-gamma resulted in hematopoietic suppression but did not cause T-bet(-/-) LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure.

Dyskeratosis congenita (DC) is an inheritable bone marrow failure syndrome characterized by reticulated hyperpigmentation, dystrophic nails and oral leukoplakia. Another name for the condition is Zinsser-Cole-Engman syndrome. Hematologic manifestations usually do not appear in childhood but later in early adulthood. Patients are also prone to carcinomas, particularly of the head and neck. The disease has X-linked or autosomal dominant/recessive inheritance. Early childhood variants (Hoyeraal-Hreidarsson syndrome) are associated with immunological abnormalities in the form of low T- and B-cell numbers. Four genes, namely DKC1 (codes for dyskerin), TERC and TERT (code for telomerase) and NOP10, have been implicated in the pathogenesis; the short telomeres provide a marker for genetic linkage studies. Androgens, with or without granulocyte colony stimulating factor, have been tried in the treatment of the conditions with variable results. Stem cell transplantation from matched sibling donor is currently the treatment of choice. It requires modified nonmyeloablative conditioning protocols, since the patients with DC are prone to pulmonary and hepatic complications.

Bone marrow transplantation (BMT) represents a cure for nonmalignant hematological disorders. However, compared with the stringent conditioning regimens used when performing BMT to treat hematological malignancies, the reduced intensity conditioning regimen used in the context of nonmalignant hematological disorders leads to substantially higher rates of BMT rejection, presumably due to an intact immune system. The relevant patient population typically receives transfusion support, often including platelets, and the frequency of BMT rejection correlates with the frequency of transfusion. Here, we demonstrate that immunity to transfused platelets contributes to subsequent BMT rejection in mice, even when the BMT donor and recipient are MHC matched. We used MHC-matched bone marrow because, although immunity to transfused platelets is best characterized in relation to HLA-specific antibodies, such antibodies are unlikely to play a role in clinical BMT rejection that is HLA matched. However, bone marrow is not matched in the clinic for minor histocompatibility antigens, such as those carried by platelets, and we report that transfusion of minor histocompatibility antigen-mismatched platelets induced subsequent BMT rejection. These findings indicate previously unappreciated sequelae of immunity to platelets in the context of transplantation and suggest that strategies to account for minor histocompatibility mismatching may help to reduce the chance of BMT rejection in human patients.

Objective: To investigate the role of perforin-mediated cell apoptosis in murine models of immune-mediated bone marrow (BM) failure., Materials and Methods: We compared C57BL/6J (B6) mice carrying a perforin gene deletion (Prf(-/-)) with wild-type (WT) controls for cellular composition in lymphohematopoietic tissues. Lymph node (LN) cells from Prf(-/-) mice were coincubated with BM cells from B10-H2(b)/LilMcdJ (C.B10) mice in an apoptosis assay in vitro. We then infused Prf(-/-) and WT B6 LN cells into sublethally irradiated C.B10 and CByB6F1 recipients with mismatches at the minor and major histocompatibility loci, respectively, in order to induce BM failure. Cellular composition was analyzed by flow cytometry., Results: Prf(-/-) mice showed normal lymphoid cell composition, but Prf(-/-) LN cells had reduced ability to induce C.B10 BM cell apoptosis in vitro. Infusion of 5 to 10 x 10(6) Prf(-/-) LN cells produced obvious BM failure in C.B10 and CByB6F1 recipients; pancytopenia and BM hypocellularity were only slightly less severe than those caused by infusion of 5 x 10(6) WT B6 LN cells. Infused Prf(-/-) LN cells showed less T-cell expansion, normal T-cell activation, and higher proportions of T cells expressing gamma-interferon, tissue necrosis factor-alpha, and Fas ligand CD178, in comparison to infused WT B6 LN cells. Fas expression was equally high in residual BM cells in recipient of both Prf(-/-) and B6 LN cells., Conclusion: Perforin deficiency alters T-cell expansion but upregulates T-cell Fas ligand expression. Perforin-mediated cell death appears to play a minor role in mouse models of immune-mediated BM failure.

Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression, respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL, serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when coincubated with C.B10-H2(b)/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sublethally irradiated CB10 mice. All donor LN cells showed significant T cell expansion and activation, but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of proapoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction.

Stem cell transplants that follow both myeloablative and non-myeloablative conditioning regimens can result in states of mixed chimerism, which can be stable over time. With widespread availability of Y chromosome FISH in sex-mismatched transplantation and DNA-based methodologies for analysis of chimerism in other donor-recipient pairs, further insights have been gained regarding the implications of the mixed chimeric state. In transplants performed for inherited and acquired marrow failure disorders, disease status can be improved with only 10-20% donor cells, and it appears that stable mixed chimerism at that level is an acceptable outcome often leading to a state of tolerance, but an increasing level of recipient cells often precedes graft rejection. In transplants performed for malignant conditions, increasing levels of mixed chimerism may indicate disease relapse, but some cases with stable levels of mixed chimerism have been compatible with prolonged remission states. Understanding when mixed chimerism is an indication of secondary graft failure or impending graft rejection vs a state of tolerance and ongoing propensity for the establishment of a graft-vs-tumor effect is often difficult with currently available technologies and immunologic assays. The ability to understand the implication of mixed chimerism of multiple cell lineages and of varied lymphocyte subsets will remain important areas for future research to best harness the immunologic and other therapeutic benefits of allogeneic transplantation.

We histologically and immunohistochemically studied 37 cases of diffuse large B-cell lymphoma (DLBCL) initially manifesting in the bone marrow (BM). We also compared these cases with the Asian variant of intravascular large B-cell lymphoma (AIVL). Histologically, the neoplastic cells of the BM mostly had large and round nuclei and formed clusters. Immunohistochemically, all cases were positive for B-cell markers. Factor VIII staining revealed neoplastic cells within the sinusoids of BM in 8 cases; however, these cells accounted for fewer than 20% of the overall neoplastic cells. In several cases, the neoplastic cells infiltrated liver, spleen, kidneys, lungs, stomach, and adrenal glands with a mainly leukemic and infrequently intravascular pattern. Although our cases share some clinical features with AIVL, we consider DLBCL initially manifesting in the BM to be a unique entity because the neoplastic cells proliferate mainly in BM, with infrequent involvement of the sinusoids and occasional leukemic infiltration in various organs.

Pure red cell aplasia (PRCA) is an acute anemia due to selective suppression of erythropoiesis. We report a case of PRCA diagnosed before the onset of primary Sjögren's syndrome (SS). A young woman, with autoimmune thyroiditis, developed polyarthritis with ANA and Rheumatoid factor positivity, diagnosed as Rheumatoid arthritis. During the time she developed anti-Ro and anti-La antibodies and deformities at proximal interphalangeal joints. After 4 years, she developed severe acute anemia, without reticolocytes: a bone marrow biopsy indicated a PRCA and she started transfusions, steroids, cyclosporin. A steroid-dependent anemia persisted. After 2 years she developed sicca, parotid swelling, fatigue, mild leukopenia, elevated serum creatinine, hypokalemia, hyposthenuria and tubular proteinuria. Lip biopsy and dacriologic tests confirmed a diagnosis of SS, while X-ray revealed a deforming non-erosive arthropathy (Jaccoud type). In present case, PRCA could be considered an autoimmune bone marrow disease within SS, whose extra-glandular manifestations onset before the sicca symptoms.

We report on bone marrow plasmacytosis in four cases of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). Pathologically, the plasma cells increased in number and accounted for 20-40% of nucleated cells of bone marrow. These plasma cells diffusely infiltrated or formed numerous clusters with 50-200 cells on histological sections. Some binuclear plasma cells and Russell bodies were seen, but all plasma cells showed mature cytomorphology. One case contained two lymphoid follicles with normal germinal centers. Immunoperoxidase studies of light chain determinants for plasma cells and their precursors demonstrated a polyclonal pattern. The immunohistochemical study revealed that there were no human herpes virus-8-positive cells. Bone marrow plasmacytosis of striking proportions may occur in a number of inflammatory conditions, chronic infections, autoimmune diseases, and hypersensitivity states. These reactive plasmacytoses, although sometimes striking, are generally composed of scattered, non-aggregated plasma cells. The four cases described here contained numerous tumor-like aggregations on mature plasma cells. Our four cases should be differentiated from plasma cell myeloma composed of mature plasma cells. However, electrophoresis generally demonstrated a broad-based polyclonal hypergammmaglobulinemia. Moreover, the immunohistochemical study revealed a polytypic nature of the plasma cells. To avoid overdiagnosis and overtreatment, it is important to be aware of the bone marrow findings of IPL.

Eosinophil responses in extraintestinal and intestinal tissues were examined in August and Sprague-Dawley rats infected with Nippostrongylus brasiliensis or Eimeria nieschulzi (or both), and in uninfected controls to test the hypothesis that E. nieschulzi suppresses the systemic N. brasiliensis-induced eosinophil response. Caudal vein blood, femoral bone marrow, bronchoalveolar lavage fluid, peritoneal lavage fluid, and duodenal and jejunal samples were collected on day 8 postinfection (PI) with E. nieschulzi, on day 16 PI of the N. brasiliensis infection, when these days coincided in the concurrently infected rats, and from uninfected controls. Differential white blood cell counts were made from blood smears and cytocentrifuged preparations, and duodenal and jejunal eosinophils per villus crypt unit were quantified. Eimeria nieschulzi significantly reduced N. brasiliensis-induced eosinophil levels in peripheral blood, lavage fluids, and duodenal and jejunal tissues in both rat strains. August and Sprague-Dawley rats monospecifically infected with N. brasiliensis and concurrently with both parasites demonstrated elevated eosinopoiesis compared with uninfected controls and rats infected with only E. nieschulzi; however, despite this, concurrently infected rats had a significantly greater level of eosinopoiesis than those infected with only the nematode. In addition, E. nieschulzi induced elevated neutrophil levels in both monospecifically and concurrently infected rats in all extraintestinal tissues examined in both rat strains, whereas lymphocyte counts decreased concomitantly. This study suggests that the intestinal coccidian E. nieschulzi has the ability to modulate the systemic inflammatory response to N. brasiliensis and that this is not a rat strain-specific phenomenon.