Impaired Humoral Immunity Research Articles

Reduced Circulating Memory B-Cells Account for Humoral Immune Defects in Multiple Myeloma, Associated with Infective Risk and Poor Vaccination Responses

Multiple myeloma (MM) is characterized by an increased risk of infection due to the immunosuppressive effect of the disease and conjointly of therapy. Furthermore, there is impaired responses to vaccination to counter the infection risk. The factors that underpin defective B-cell homeostasis and effective humoral immunity are not clear, nor are the extent of the defects. Also, the level of impaired humoral immunity in MGUS is not fully understood. The aim of this study was to delineate the circulating B-cell populations and recall antibody responses in patients with MGUS & MM, compared to age-matched controls, correlating with the responsiveness to vaccinations, incidence of infective complications and concomitant therapy. We performed comprehensive B-cell immunophenotyping by multi-parameter flow cytometry of peripheral blood samples from patients with MGUS (n=16), asymptomatic MM (n=18) and MM (n=108) with a median age of 63 years (range 38-94) comparing them to age-matched controls (n=9). B-cell subsets included naïve (CD19+CD27-), memory (CD19+CD27+; non-switch CD19+IgD+CD27+, switch CD19+IgD-CD27+), transitional (CD19+CD27-CD24hiCD38hi) & regulatory (CD19+CD27+CD24hi) B-cells. Serum uninvolved total IgG, IgM & IgA levels along with vaccine-specific antibody responses were analysed. There is a progressive decrease in the uninvolved immunoglobulin classes with significant reduction in total IgA (p=0.006) and IgM levels (p=0.007) in aMM/MM compared to MGUS & control (Figure 1). When anti-pneumococcal antibodies were measured, only 30% of aMM/MM patients had adequate protective levels compared to 79% of age-matched controls, with 40% of aMM/MM patients with inadequate levels experiencing recurrent respiratory tract infections compared to 25% of aMM/MM patients with adequate proactive antibodies. Patients with MGUS, aMM and MM have lower total B-cell numbers compared to controls (1-way ANOVA p=0.004; Figure 1). The reduction in B-cell numbers were primarily the consequence of reduced memory B-cells (percentage and absolute 1-way ANOVA p<0.0001), noted in both MGUS and aMM/MM but a progressive reduction with increasing disease activity (MGUS>aMM>MM). Furthermore, a correlation with total IgG levels & memory B-cell numbers is evident (r2=-0.053) & progressive reduction in memory B-cell numbers is seen with advancing cycles of therapy. The ratio of switch:non-switch memory B-cells is unaltered (control 1.05, MGUS 0.53, aMM 1.41 & MM 1.49; 1-way ANOVA p=ns). Conversely, there is a compensatory increase in the percentage of transitional B-cells when increasing disease stage is compared to controls (control 7.38% (95%ci 4.9,9.9) vs MGUS 14.0% (95%ci 7.4, 20.7) vs aMM 14.95% (95%ci 8, 21.9); 1-way ANOVA p<0.001) but a reduction is noted in MM (5.82%, 95%ci 4.5,7.2; p<0.0001), primarily being driven by sequential lines of therapy. As a consequence, the ratio of Memory:transitional B-cells is significantly reduced in aMM/MM compared to MGUS & controls (control 10.35, MGUS 20.46, aMM 7.74 & MM 4.57; 1-way ANOVA p=0.006), associated with increasing incidence of bacterial infections. A non-significant correlation is seen between transitional B-cells and total uninvolved immunoglobulin levels and with recall responses to vaccinations. There is a progressive decrease in the CD19+CD27+CD24hi B-cell subset between control and plasma cell dyscrasias (control 20.4% (95%ci 15.5,25.2), MGUS 14.0% (95%ci 7.4, 20.7), aMM 14.95% (95%ci 8, 21.9) & MM 5.82%, 95%ci 4.5,7.2; p<0.0001), primarily being driven by sequential lines of therapy and associated with increased incidence of infection. This study illustrates that patients with myeloma demonstrate reduced total circulating B-cells primarily as a consequence of reduced memory B-cells, associated with reduced immunoglobulin and recall antibody responses. This is associated with increased incidence of bacterial infections and is worsened by sequential exposure to lymphodepleting therapies. Of particular importance is the identified aberration in B-cell subsets seen in MGUS compared with age-matched control, indicative of humoral immune dysregulation highlighting that MGUS may not be an immunologically inert disorder. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Human T follicular helper cells in primary immunodeficiencies.

To summarize our understanding of the biology of T follicular helper (Tfh) cells and how insights into this are being provided by the study of human monogenic immunological diseases. Antibody production is a key feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Long-lived humoral immunity depends on help provided by Tfh cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. Tfh cells are generated from naïve CD4 T cells following the receipt of inputs from various cell surface receptors. Although genetically modified mice have provided a great understanding of the requirements for generating Tfh cells, it is critical that the requirements for human Tfh cells are also established. This is being achieved by the systematic analysis of humans with monogenic mutations that cause primary immunodeficiencies characterized by impaired humoral immunity following infection or vaccination. The elucidation of the mechanisms that regulate Tfh cell generation, differentiation and function should reveal targets for novel therapeutics that may offer opportunities to manipulate these cells to not only improve humoral immunity in the setting of primary immunodeficiencies but also temper their dysregulation in conditions of antibody-mediated autoimmunity.

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Intensive chemotherapy in children with cancer results in long-term impairment of humoral immunity. Whereas most studies to date focused on children with acute lymphoblastic leukemia (ALL), little data have been published on patients suffering from Hodgkin disease or from solid tumors. We therefore analyzed the loss of protective immunity (defined as immunity at the time of diagnosis and lack of immunity after completion of therapy) against vaccine-preventable diseases in children treated for various malignancies.Children and adolescents <21 years of age at diagnosis and treated between 2001 and 2010 for various malignancies in the Department of Pediatric Hematology and Oncology, University of Frankfurt, were included in the retrospective chart review. Antibody levels against measles, mumps, rubella and varicella-zoster-virus (VZV) were routinely assessed at the time of diagnosis and within 12 months after completion of therapy.The study population consisted of 195 children (122 male); 80 patients had ALL, 15 acute myelogenous leukemia (AML), 18 non-Hodgkin lymphoma (NHL), 22 Hodgkin disease, and 60 various solid tumors. Overall, 27%, 47%, 19%, and 17% of the patients lost their humoral immunity against measles, mumps, rubella, and VZV, respectively. The risk of losing protective antibody titers depended on age with a higher risk in younger children. The loss of protective humoral immunity occurred significantly more often in patients with ALL compared to patients with any other underlying malignant disease (hematological malignancies such AML and NHL, Hodgkin disease or solid tumors).Our data demonstrate that a significant number of children lose pre-existing humoral immunity against measles, mumps, rubella, and VZV after completion of chemotherapy. This loss occurs more often in children with ALL than in children with AML, solid tumors and Hodgkin disease. Our results underline the need for post-chemotherapy revaccination of childhood cancer survivors.

Juvenile idiopathic arthritis in a child with nijmegen breakage syndrome

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive DNA repair disorder, caused by mutation in the NBS1 gene on chromosome 8q21. The hallmark symptom is microcephaly, other characteristic features are facial phenotype, growth retardation, premature ovarian failure in girls. Psychomotor development is usually not disturbed. Impaired cellular and humoral immunity is essential feature of syndrome. Patients with NBS have an extremely high risk for developing malignancy.

Defective B-cell memory in patients with Down syndrome

Patients with Down syndrome carry immunologic defects, as evidenced by the increased risks for autoimmune diseases, hematologic malignancies, and respiratory tract infections. Moreover, the low numbers of circulating B cells suggest impaired humoral immunity. We sought to study how immunodeficiency in patients with Down syndrome results from immunologic defects in the B-cell compartment. We studied blood B-cell subset composition, replication history, somatic hypermutation status, and class-switch recombination in 17 children with Down syndrome. Germinal centers and plasma cells were studied in tonsils from 4additional children with Down syndrome. Blood transitional B-cell numbers were normal, but naive mature and memory B-cell numbers were reduced despite slightly increased serum B cell-activating factor levels. Germinal centers and plasma cells in tonsils appeared normal, as were serum immunoglobulin levels. CD27(+)IgD(+)IgM(+) "natural effector" B cells showed reduced proliferation and somatic hypermutation levels, whereas these were normal in CD27(+)IgD(-) memory B cells. Furthermore, IgM(+) and IgA(+), but not IgG(+), memory B cells showed impaired molecular signs for antigen selection. The B-cell pattern was highly similar to that of patients with common variable immunodeficiency and a defect in B-cell activation and proliferation. Children with Down syndrome seem capable of normal germinal center and plasma cell formation. Still, blood memory B-cell numbers were reduced and showed impaired molecular maturation of IgA and IgM, which are important for mucosal immunity. The observed molecular defects in circulating IgA and IgM B-cell memory could reflect impaired local responses, which underlie the increased susceptibility torespiratory tract infections of patients with Down syndrome.

XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP.

X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency affecting approximately 1-2 per 1 million males. A key feature of XLP is the exquisite sensitivity of affected individuals to disease induced following EBV infection. However, patients can also develop hypogammaglobulinemia and B-cell lymphoma independently of exposure to EBV. XLP is caused by loss-of function mutations in SH2D1A, which encodes the intracellular adaptor molecule SAP. SAP is predominantly expressed in T cells and NK cells, and functions to regulate signal transduction pathways downstream of the SLAM family of surface receptors to control CD4+ T cell (and by extension B cells), CD8+ T cell and NK cell function, as well as the development of NKT cells. The study of XLP had shed substantial light on the requirements for lymphocyte differentiation and immune regulation, which in turn have the potential to be translated into novel treatments for not only XLP patients but individuals affected by EBV-induced disease, impaired humoral immunity and malignancy.

Double negative (CD19+IgG+IgD−CD27−) B lymphocytes: A new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer's disease patients

Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD−CD27− (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (α-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate–severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.

Differential loss of humoral immunity against measles, mumps, rubella and varicella-zoster virus in children treated for cancer

BackgroundIntensive chemotherapy in children with cancer results in long-term impairment of humoral immunity. Whereas most studies to date focused on children with acute lymphoblastic leukemia (ALL), little data have been published on patients suffering from Hodgkin disease or from solid tumors. We therefore analyzed the loss of protective immunity (defined as immunity at the time of diagnosis and lack of immunity after completion of therapy) against vaccine-preventable diseases in children treated for various malignancies. MethodsChildren and adolescents <21 years of age at diagnosis and treated between 2001 and 2010 for various malignancies in the Department of Pediatric Hematology and Oncology, University of Frankfurt, were included in the retrospective chart review. Antibody levels against measles, mumps, rubella and varicella-zoster-virus (VZV) were routinely assessed at the time of diagnosis and within 12 months after completion of therapy. ResultsThe study population consisted of 195 children (122 male); 80 patients had ALL, 15 acute myelogenous leukemia (AML), 18 non-Hodgkin lymphoma (NHL), 22 Hodgkin disease, and 60 various solid tumors. Overall, 27%, 47%, 19%, and 17% of the patients lost their humoral immunity against measles, mumps, rubella, and VZV, respectively. The risk of losing protective antibody titers depended on age with a higher risk in younger children. The loss of protective humoral immunity occurred significantly more often in patients with ALL compared to patients with any other underlying malignant disease (hematological malignancies such AML and NHL, Hodgkin disease or solid tumors). ConclusionsOur data demonstrate that a significant number of children lose pre-existing humoral immunity against measles, mumps, rubella, and VZV after completion of chemotherapy. This loss occurs more often in children with ALL than in children with AML, solid tumors and Hodgkin disease. Our results underline the need for post-chemotherapy revaccination of childhood cancer survivors.

Identification of a new isoform of the murine Sh2d1a gene and its functional implications

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is a Src homology (SH) domain 2-containing intracellular adaptor protein that is predominantly expressed in the hematopoietic system by T lymphocytes and NK cells. SAP protein is encoded by the SH2D1A gene located on the X chromosome. Loss-of-function mutations in SAP cause the X-linked lymphoproliferative disease (XLP), a severe immunodeficiency characterized by heightened susceptibility to Epstein-Barr virus and impaired humoral immunity. Normal individuals express several functional and non-functional isoforms of SAP as a result of alternative splicing. In this study, we identify a cryptic exon in the murine Sh2d1a gene. At the mRNA level, the new isoform of SAP (SAP-2) that includes this new exon is widely expressed in lymphoid tissues by C57BL/6 and 129 strains of inbred mice. SAP-2 accounts for approximately 1%-3% of total SAP transcripts, and it is dynamically regulated during lymphocyte activation. At the protein level, the SAP-2 isoform is a 144 amino-acid protein. Compared to the dominant 126 aminoacid SAP-1 isoform, the additional 18 amino acids are inserted into a structural region that is critical for phosphotyrosine binding. Our functional analysis in vitro indicates that SAP-2 is a non-functional isoform due to decreased protein stability. Thus, both human and mouse have multiple SAP splice isoforms that may or may not function. Modulation of relative proportions of these isoforms is potentially a mechanism whereby cells can regulate SAP-mediated biological activities.

Clinical Features, Outcome and Prognostic Factors For Survival and Evolution To Multiple Myeloma Of Solitary Plasmacytomas: A Report Of The Greek Myeloma Study Group In 97 Patients

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary tumors consisting of monoclonal plasma cells, without evidence of systematic multiple myeloma (MM). The treatment of choice is local radiotherapy (RT) with or without surgical excision (SE). Our aim was to describe the clinical features, the outcome and prognosis of SP patients. Thus, we studied 97 consecutive patients, 65 with solitary bone plasmacytoma (SBP) and 32 with solitary extramedullary plasmacytoma (SEP), (M/F: 66/31, median age: 61 years, range 17-85 years) who were diagnosed and treated in 12 Greek Myeloma Centers; treatment was given according to each center's local policy.Patients with SBP and SEP did not differ in age, gender, performance status (PS), Hb, CRP, LDH, calcium, beta2-microglobulin, renal function or impairment of humoral immunity (immunoparesis). Patients with SEP presented more often with serum or urinary monoclonal component (p<0.001 and p=0.004, respectively). The median size of SP was larger in patients with SBP compared to patients with SEP (5.5cm vs. 3cm; p=0.003). CD56 antigen was expressed more often on plasma cells of SBP biopsies (p=0.03). Eighteen (56.2%) patients with SEP presented with upper respiratory track plasmacytoma and 14 presented with plasmacytomas in other locations. In 26/65 patients (40%) with SBP, plasmacytoma was located in the vertebrae and 39 had plasmacytoma in other bones. Bisphosphonates were administered more frequently in SBP patients (p=0.001). There was no difference in the type of treatment (RT, conventional chemotherapy (CT) ± novel agents (NA), SE or combined treatment) between the 2 groups; 80 patients (82.5%) received RT alone or in combination with CT and/or SE, 7 patients (7.2%) received CT alone, 7 patients (7.2%) underwent only SE and 3 patients (3.1%) were treated with CT and SE. The median dose of radiation delivered was 40 Gy (range 24-55 Gy). Novel agent combinations were administered in 27/47 patients (57.4%) who received CT (bortezomib-based regimens: 46.8%); 13/47 (27.6%) patients treated with CT underwent high-dose therapy. Myelotoxicity, neurotoxicity and neutropenic infections presented more frequently in patients treated with CT (p<0.001, p=0.01, p=0.009, respectively). Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively. There was no difference in response rates or median time to response (3 months, range 1-24 months) between patients with SBP or SEP. Overall, 38 (39.2%) patients relapsed (relapse of SP only: 14; progression to MM only: 16, relapse of SP and progression to MM: 8). After a median follow up of 60 months (range 3-264 months), 74 (76.3%) patients were alive, 13 (13.4%) were dead and 10 (10.3%) patients were lost to follow up. Overall survival (OS), although higher in SEP over SBP, did not reach statistical significance. The 10-year MM-free survival (MMFS) was 50% vs. 70% respectively, for patients with SBP vs. SEP (p=0.054). Ten-year OS for patients treated with RT± surgical excision was 81% vs. 70% for those treated with other therapies including CT± NA (p=0.3). Overall, the 10-year OS, plasmacytoma relapse-free survival (PRFS), progression-free survival (PFS) and MMFS was 78%, 58%, 43% and 59%, respectively. In the multivariate analysis PRFS and age predicted for OS (p=0.02, HR: 0.97; 95% CI: 0.94-0.99 and p=0.01, HR: 1.09; 95% CI: 1.017-1.16, respectively); 10-year OS for patients <60 vs. ≥60 years was 85% vs. 60% (p=0.02); patients with PRFS >24 vs. ≤24 months had a 10-year OS of 82% vs. 60% (p=0.01). Achievement of CR predicted positively for PRFS. Immunoparesis (n=24) predicted negatively for progression to MM. Chemotherapy including NA had no prognostic impact on OS, PRFS or MMFS.Our study demonstrated that patients with SP enjoy a prolonged OS that is favorably influenced by young age and PRFS. We also confirmed that patients with SBP progress more frequently to MM compared to SEP in the era of novel agents. Radiotherapy with or without SE remains the treatment of choice for SP. The additional use of systematic therapy including novel anti-myeloma agents increases toxicity without improving survival or decreasing the probability of SP relapse or progression to MM. Immunoparesis predicts for progression to MM. Disclosures:No relevant conflicts of interest to declare.

Clinical Responses In Patients Infused With T Lymphocytes Redirected To Target κ-Light Immunoglobulin Chain

Adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) to treat B-cell malignancies shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, causes sustained depletion of normal B cells and consequent severe hypogammaglobulinemia. In order to target B-cell malignancies more selectively, we exploited the clonal restriction of mature B-cell malignancies, which express either a κ or a λ-light immunoglobulin (Ig) chain. We generated a CAR specific for κ-light chain (CAR.κ) to selectively target κ+ lymphoma/leukemia cells, while sparing the normal B cells expressing the reciprocal λ-light chain, thus minimizing the impairment of humoral immunity. After preclinical validation, we designed a phase I clinical trial in which patients with refractory/relapsed κ+ non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) are infused with autologous T cells expressing a CAR.κ that includes a CD28 costimulatory domain. The protocol also included patients with multiple myeloma with the aim of targeting putative myeloma initiating cells. Three dose levels (DL) are being assessed, with escalation determined by a continual reassessment method: 0.2 (DL1), 1 (DL2) and 2 (DL3) ×108 T cells/m2. Repeat infusions are allowed if there is at least stable disease after treatment. End points being evaluated include safety, persistence of CAR+T cells and antitumor activity.T cells were generated for 13 patients by activating autologous PBMC with immobilized OKT3 (n=5) or CD3/CD28 monoclonal antibodies (n=8). In 2 patients with >95% circulating leukemic cells, CD3 positive selection was performed using CliniMACS. After transduction, T cells (1.2×107±0.5×107) were expanded ex vivo for 18±4 days in the presence of interleukin (IL)-2 to reach sufficient numbers for dose escalation. CAR expression was 81%±13% by flow cytometry (74,112±23,000 transgene copy numbers/mg DNA). Products were composed predominantly of CD8+ cells (78%±10%), with a small proportion of naïve (5±4%) and memory T cells (17%±12%). CAR+ T cells specifically targeted κ+ tumors as assessed by 51Cr release assays (specific lysis 79%±10%, 20:1 E:T ratio) but not κ–tumors (11%±7%) or the NK-sensitive cell line K562 (26%±13%).Ten patients have been treated: 2 on DL1, 3 on DL2 and 5 on DL3. Any other treatments were discontinued at least 4 weeks prior to T-cell infusion. Patients with an absolute leukocyte count >500/µL received 12.5 mg/kg cyclophosphamide 4 days before T-cell infusion to induce mild lymphopenia. Infusions were well tolerated, without side effects. Persistence of infused T cells was assessed in blood by CAR.κ-specific Q-PCR assay and peaked 1 to 2 weeks post infusion, remaining detectable for 6 weeks to 9 months. Although the CAR contained a murine single-chain variable fragment (scFv), we did not detect human anti-mouse antibodies following treatment and CAR.κ+T cell expansion continued to be observed even after repeated infusions. We detected modest (<20 fold) elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells, but systemic inflammatory response syndrome (cytokine storm) was absent. No new-onset hypogammaglobulinemia was observed.All 10 patients are currently evaluable for clinical response. Of the patients with relapsed NHL, 2/5 entered complete remission (after 2 and 3 infusions at dose level 1 and 3, respectively), 1/5 had a partial response and 2 progressed; 3/3 patients with multiple myeloma have had stable disease for 2, 8 and 11 months, associated with up to 38% reduction in their paraprotein; and 2/2 patients with CLL progressed before or shortly after the 6-week evaluation. In conclusion, our data indicate that infusion of CAR.κ+ T cells is safe at every DL and can be effective in patients with κ+ lymphoproliferative disorders. Disclosures:Savoldo:Celgene: Patents & Royalties, Research Funding. Rooney:Celgene: Patents & Royalties, Research Funding. Heslop:Celgene: Patents & Royalties, Research Funding. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding.

Rituximab for the Treatment of Follicular Lymphoma

Rituximab is the first and most widely adopted anti-CD20 monoclonal antibody, and has dramatically improved outcomes for patients with B-cell malignancies. Rituximab is active as a single agent and when combined with chemotherapy improves both response rates and survival compared with chemotherapy alone. This approach has become standard of care in this setting. A number of Phase III studies using extended applications of rituximab have demonstrated that patients achieve a significantly longer progression-free survival, at the cost of an increase in infective complications. This has resulted in the widespread adoption of maintenance rituximab following the completion of primary therapy. Rituximab is useful in both previously untreated patients and at relapse, although a subset of patients develop disease that is rituximab resistant, which along with histologic transformation remains a significant management problem for patients with follicular lymphoma. The toxicities are modest and manageable, including infusion reactions, late-onset neutropenia, impaired humoral immunity, reactivation of hepatitis and possibly pulmonary toxicity.

Immunological Parameters of the Blood and Monoamine Content in the Brain of Rats during Long-Term Overcrowding

Blood immunological parameters (cytokine profile and interferon status) and the level of monoamines and their metabolites in various brain structures (amygdala, hippocampus, septum, and hypothalamus) were studied in rats kept under standard conditions or in overpopulated cages. Long-term overcrowding was associated with reduced expression of IL-4 gene, increased transcription of IL-17, and decreased production of IFN-γ, which attested to impaired humoral and cell-mediated immunity and disturbances in IFN-γ synthesis at the post-transcriptional level. Under these conditions, the levels of norepinephrine and dopamine decreased in the septum, but increased in the hypothalamus. The amount of dopamine metabolite dihydroxyphenylacetic acid decreased in both these structures, and the index of dopamine metabolism (dihydroxyphenylacetic acid/dopamine ratio, DOPAC/dopamine) decreased only in the hypothalamus. Overcrowding was not followed by changes in the parameters of noradrenergic and dopaminergic systems in the amygdala and hippocampus and serotoninergic system in all study structures.

Immunostimulatory effect of a composition isolated from white peony root oral liquid in the treatment of radiation-induced esophagitis

The aim of this study was to explore the immune repairing effect of a composition isolated from white peony root oral liquid (cWPROL), a traditional Chinese herbal composition, in the treatment of experimental radiation-induced esophagitis in rats. A total of 128 Wistar rats were randomly divided into eight groups, irradiated with 43 Gy 60Co γ-rays to induce esophagitis and treated by different methods. Flow cytometry, hematological analysis and immune nephelometry were used to detect the absolute numbers and percentages of CD3+, CD4+ and CD8+ T lymphocytes, numbers and classification of leukocytes, and the levels of IgG and complement C3 in the peripheral blood of the rats at each experimental time point. Following irradiation, the total number of leukocytes, absolute numbers and percentages of CD3+, CD4+ and CD8+ T lymphocytes, and levels of IgG and complement C3 in the peripheral blood of the rats were decreased. Furthermore, the total numbers of leukocytes, absolute numbers and percentages of CD3+, CD4+ and CD8+ T lymphocytes, and levels of IgG and complement C3 in the peripheral blood were higher in the administered with cWPROL by intra-esophageal perfusion compared with those in the untreated irradiated groups, but lower in the groups treated with a mixture of lidocaine hydrochloride, dexamethasone sodium phosphate and gentamicin sulfate. This study suggested that cWPROL is able to repair the impaired cellular and humoral immunity of rats with radiation-induced esophagitis.

Nucleoprotein‐specific nonneutralizing antibodies speed up LCMV elimination independently of complement and FcγR

CD8(+) T cells have an essential role in controlling lymphocytic choriomeningitis virus (LCMV) infection in mice. Here, we examined the contribution of humoral immunity, including nonneutralizing antibodies (Abs), in this infection induced by low virus inoculation doses. Mice with impaired humoral immunity readily terminated infection with the slowly replicating LCMV strain Armstrong but showed delayed virus elimination after inoculation with the faster replicating LCMV strain WE and failed to clear the rapidly replicating LCMV strain Docile, which is in contrast to the results obtained with wild-type mice. Thus, the requirement for adaptive humoral immunity to control the infection was dependent on the replication speed of the LCMV strains used. Ab transfers further showed that LCMV-specific IgG Abs isolated from LCMV immune serum accelerated virus elimination. These Abs were mainly directed against the viral nucleoprotein (NP) and completely lacked virus neutralizing activity. Moreover, mAbs specific for the LCMV NP were also able to decrease viral titers after transfer into infected hosts. Intriguingly, neither C3 nor Fcγ receptors were required for the antiviral activity of the transferred Abs. In conclusion, our study suggests that rapidly generated nonneutralizing Abs specific for the viral NP speed up virus elimination and thereby may counteract T-cell exhaustion.

Septic Arthritis Due to Haemophilus influenzae Serotype f in a Patient With Waldenström Macroglobulinemia

In Brief Haemophilus influenzae, a gram-negative pleomorphic bacillus, is a well- recognized pathogen in children. In recent years, it is increasingly recognized as an opportunistic pathogen in adults predominantly causing bacteremia, pneumonia, or meningitis. Impaired humoral immunity is a major factor in the development of more invasive infections. An extensive review of the literature reveals that it is infrequently identified as the etiologic agent of septic arthritis in adults. Initial management of septic arthritis includes surgical drainage and antibiotic therapy. We present a case of septic arthritis due to H influenzae serotype f in a patient with Waldenström macroglobulinemia. After surgical drainage and 3 weeks of antibiotic therapy, the patient resumed normal activity and has continued to do well after 1 year of follow-up. Physicians must be mindful of this invasive pathogen’s role in septic arthritis and the need for immediate surgical intervention and antibiotic administration so as to decrease associated morbidity and mortality. Since the introduction of the Hib vaccine, the overall incidence of Haemophilus influenzae infection has decreased among children with a subsequent increased incidence of invasive disease in adults. A majority of invasive infections are now identified as serotype f and other nontypable strains. Carlsen et al. present a case of septic arthritis due to H.influenzae, serotype f in a patient with Waldenström macroglobulinemia. Patients with underlying immunodeficiencies are especially prone to this relatively rare phenomenon. Physicians must remain vigilant in entertaining this diagnosis in patients with immunodeficiencies so as to prevent associated morbidity and mortality.

Occurrence of autoantibodies for gastrointestinal autoimmune diseases in children with common variable immune deficiency and selected IgA deficiency.

IntroductionSelected IgA deficiency (IgAD) and common variable immune deficiency (CVID) are humoral immunity deficiencies frequent in children. In both these types of immunodeficiency, autoimmune diseases are present in 20–30% of patients, but the disease profiles are different between adults and children. Autoimmune diseases of the gastrointestinal tract (IBD) and celiac disease are typical for children with IgAD and CVID. Diagnosis is based on clinical symptoms, histology of jejunum and antibodies often preceding the onset of disease. However, the diagnosis of IBD and celiac disease is difficult in immune deficiency patients due to weaker or absent production of antibodies, and different jejunum histology, particular in CVID patients.AimDetection of antibodies for autoimmune diseases in children with diagnosis of CVID and IgAD.Material and methodsThe study included 43 children with CVID and 63 children with IgAD diagnosis. Antibodies typical for celiac disease (for endomysium, tissue transglutaminase and gliadin) were tested in IgA class (CVID patients), IgG class (IgAD, CVID patients) and found in 16 patients (3 – CVID, 13 – IgAD).ResultsAntibodies for IBD (for Saccharomyces cerevisiae antigen – ASCA, goblet cells – Gab, neutrophil’s cytoplasm – ANCA, pancreatic cells – Pab) were noted in 17 patients (7 – CVID, 10 – IgAD). Celiac disease was diagnosed in two children with mild and unspecific clinical symptoms followed by introduction of a gluten-free diet. The remaining children with present antibodies but without clinical symptoms involving the gastrointestinal tract are under careful clinical observation with antibody assay every 6 months.ConclusionsThe antibodies are produced despite impaired humoral immunity but the level might be low so the lower limit of positive results is postulated.

Disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient

Toxoplasmosis is increasingly diagnosed after hematopoietic stem cell transplantation (HSCT) and is associated with considerable morbidity and mortality. In the majority of cases, reactivation of latent disease secondary to impaired cellular and humoral immunity after HSCT is believed to be the main pathogenetic mechanism. Hence, primary toxoplasmosis is rarely considered in the differential diagnosis of infections after HSCT in a recipient who is seronegative for Toxoplasma gondii pre-transplant. We herein report a seronegative patient with acute T-cell lymphoblastic leukemia, who developed primary disseminated toxoplasmosis 5 months after HSCT from a seronegative unrelated donor. A review of all reported cases of primary toxoplasmosis after HSCT revealed significantly increased morbidity and mortality. Patients with negative pre-transplant Toxoplasma serology should therefore be considered at risk for toxoplasmosis after allogeneic HSCT. Possible prevention and monitoring strategies for seronegative recipients are reviewed and discussed in detail.

Effects of human intravenous immunoglobulin on amyloid pathology and neuroinflammation in a mouse model of Alzheimer’s disease

BackgroundHuman intravenous immunoglobulin (hIVIG) preparation is indicated for treating primary immunodeficiency disorders associated with impaired humoral immunity. hIVIG is known for its anti-inflammatory properties and a decent safety profile. Therefore, by virtue of its constituent natural anti-amyloid beta antibodies and anti-inflammatory effects, hIVIG is deemed to mediate beneficial effects to patients of Alzheimer’s disease (AD). Here, we set out to explore the effects of hIVIG in a mouse model of AD.MethodsWe treated APP/PS1dE9 transgenic and wild-type mice with weekly injections of a high hIVIG dose (1 g/kg) or saline for 3 or 8 months. Treatment effect on brain amyloid pathology and microglial reactivity was assessed by ELISA, immunohistochemistry, RT-PCR, and confocal microscopy.ResultsWe found no evidence for reduction in Aβ pathology; instead 8 months of hIVIG treatment significantly increased soluble levels of Aβ40 and Aβ42. In addition, we noticed a significant reduction in CD45 and elevation of Iba-1 markers in specific sub-populations of microglial cells. Long-term hIVIG treatment also resulted in significant suppression of TNF-α and increase in doublecortin positive adult-born neurons in the dentate gyrus.ConclusionsOur data indicate limited ability of hIVIG to impact amyloid burden but shows changes in microglia, pro-inflammatory gene expression, and neurogenic effects. Immunomodulation by hIVIG may account for its beneficial effect in AD patients.

Complications of immunosuppressive/immunomodulatory therapy in neurological diseases.

The first critical step in the appropriate treatment of neurological infectious disease accompanying immunosuppressive states or immunomodulatory medication is to properly identify the offending organism. Broadly immunosuppressive conditions will predispose to both common and uncommon infectious diseases. There are substantial differences between neurological infectious disorders complicating disturbances of the innate immunity (neutrophils, monocytes and macrophages) and those due to abnormal adaptive immunity (humoral and cellular immunity). Similarly, there are differences in the types of infections with impaired humoral immunity compared to disturbed cellular immunity and between T- and B-cell disorders. HIV/AIDS has been a model of acquired immunosuppression and the nature of opportunistic infections with which it has been associated has been well characterized and generally correlates well with the degree of CD4 lymphopenia. Increasingly, immunotherapies target specific components of the immune system, such as an adhesion molecule or its ligand or surface receptors on a special class of cells. These targeted perturbations of the immune system increase the risk of particular infectious diseases. For instance, natalizumab, an α4β1 integrin inhibitor that is highly effective in multiple sclerosis, increases the risk of progressive multifocal leukoencephalopathy for reasons that still remain unclear. It is likely that other therapies that result in a disruption of a specific component of the immune system will be associated with other unique opportunistic infections. The risk of multiple simultaneous neurological infections in the immunosuppressed host must always be considered, particularly with a failure to respond to a therapeutic regimen. With respect to appropriate and effective therapy, diagnostic accuracy assumes primacy, but occasionally broad spectrum therapy is necessitated. For a number of opportunistic infectious disorders, particularly some viral and fungal diseases, antimicrobial therapy remains inadequate.