A case report of biclonal immunoglobulin D lambda/lambda multiple myeloma in patient with liver echinococcosis.

Less than 2% of all symptomatic multiple myeloma (MM) has immunoglobulin D (IgD) as monoclonal protein. Biclonal gammopathy is much rarer. At the time of diagnosis, disease is often in advanced stage, including renal failure, anemia, hypercalcemia and lytic bone lesions. Due to the rarity of myeloma itself, but also due to the fact that anti-IgD antisera is not used in routine practice, there are only a few reports of IgD MM described in the literature. This case report describes a patient with IgD lambda MM with anemia and renal failure. Anemia, renal failure, and > 80 percent plasma cells in bone biopsy in our patient with IgD lambda MM meets International Myeloma Working Group criteria for diagnosis of MM. The patient clinical course was similar to other patients with IgD MM. The final result of serum protein immunofixation (s-IFE) showed IgD lambda and free lambda monoclonal bands. To prevent misdiagnosis, it is necessary to use anti-IgD and anti-IgE antisera whenever the serum protein immunofixation with IgA, IgM, IgG, kappa and lambda antiserums shows a kappa or lambda monoclonal band without monoclonal band in heavy chain.

A case of benign immunoglobulin D monoclonal gammopathy of undetermined significance with 26 years of follow-up.

The presence of a serum immunoglobulin D (IgD) monoclonal protein (M-protein) is seen in < 1% of patients with monoclonal gammopathies and is usually indicative of a malignant plasma cell disorder. Only a few cases of well-documented benign monoclonal gammopathy of undetermined significance (MGUS) of IgD subtype have been reported, and only 2 of those had over 5 years of follow-up at the time they were reported. Herein we describe longer-term follow-up of one of those 2 patients who has subsequently passed away from unrelated causes but never developed multiple myeloma or amyloidosis after 26 years of follow-up. Although IgD MGUS is extremely rare, this case confirms that presence of an IgD M-Protein is not always synonymous with a malignant plasma cell process.

The dual aspects of IgD in the development of tolerance and the pathogenesis of allergic diseases.

The cell-surface form of IgD is co-expressed with IgM on mature, naïve B cells as B-cell receptors. The secreted IgD antibody (Ab) is found in relatively modest concentrations in the blood and other body fluids as it has a relatively short serum half-life. IgD Abs produced in the upper-respiratory mucosa presumably participate in host defense against pathogens. The allergen-mediated cross-linkage of basophil-bound IgD Ab enhances type 2 cytokine secretion; IgD Ab may also interfere with IgE-mediated basophil degranulation, suggesting dual and opposing roles of IgD Ab in allergen sensitization and the development of allergen immune tolerance. We recently demonstrated that children with egg allergies who avoided all forms of egg have lower ovomucoid-specific IgD and IgG4 Ab levels than those who only partially avoided egg products and that different mechanisms may regulate allergen-specific IgD Ab production compared to allergen-specific IgG4 Ab production. The relationship between antigen-specific IgD Ab levels and the clinical improvement of asthma and food allergies suggests that antigen-specific IgD Ab affects the process of outgrowing allergies. We discuss the possibility that allergen-specific IgD Ab production reflects low-affinity, allergen-specific IgE production as children outgrow a food allergy.

Two Siblings With Recurrent Fevers: The Path to Mevalonate Kinase Deficiency Diagnosis.

Systemic autoinflammatory diseases (SAIDs) are a group of disorders that constitute a rare cause of recurrent fevers. Recurrent fevers are defined as periodic febrile episodes lasting from days to weeks, separated by symptom-free intervals of variable duration. They present multiple etiologies, representing a diagnostic challenge. Mevalonate kinase deficiency (MKD) is a genetic SAID, a rare hereditary recurrent fever syndrome (HRF) caused by pathogenic variants in the mevalonate kinase (MVK) gene. It is characterized by the early onset of periodic fever flares, frequently associated with joint, gastrointestinal, skin, and lymph node involvement. Although elevated serum immunoglobulin D (IgD) levels were previously considered an MKD's hallmark, normal values do not exclude it. High serum immunoglobulin A (IgA) is frequent. An acute-phase response and elevated urinary mevalonic acid (UAV) excretion during flares may aid in the diagnosis. Genetic testing is an essential tool to confirm the diagnosis. The authors report two siblings presenting with early infancy onset of recurrent febrile illness and characteristic associated symptoms, one of which was initially misdiagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. MKD diagnoses were only established at 12 and nine years old, respectively, after the identification of the same two MVKgene variants. The diagnosis in the eldest favored the earlier recognition of MKD in the youngest. Owing to its wide spectrum of manifestations, with many being nonspecific and/or shared with other more frequent entities, a significant proportion of MKD patients present a long delay until its final establishment. These cases illustrate the MKD diagnosis and management's difficulties, reinforcing the importance of a careful clinical history and HRF awareness for its prompt diagnosis and appropriate precocious referral.

IgD/FcδR is involved in T-cell acute lymphoblastic leukemia and regulated by IgD-Fc-Ig fusion protein.

T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Excessive IgD may play a role in T cell activation via IgD Fc receptor (FcδR). Here we aimed to investigate the effects of IgD in T-ALL and demonstrated the potential benefit by targeting IgD/FcδR in T-ALL patients with IgD-Fc-Ig fusion protein. In T-ALL patients' blood samples and cell lines, the level of IgD, the percentage of FcδR expressing cells and the binding affinity were determined by flow cytometry. T cell viability, proliferation and apoptosis were analyzed. A mouse xenograft model was used to evaluate the in vivo effect of IgD-Fc-Ig, an IgD-FcδR blocker. The levels of serum IgD and FcδR were abnormally increased in part of T-ALL patients and IgD could induce over-proliferation and inhibit apoptosis of T-ALL cells in vitro. FcδR was constitutively expressed on T-ALL cells. IgD-Fc-Ig showed similar binding affinity to FcδR and selectively blocked the stimulation effect of IgD on T-ALL cells in vitro. In vivo study exhibited that IgD-Fc-Ig may also have therapeutic benefit. IgD-Fc-Ig administration inhibited human T-ALL growth and extended survival in xenograft T-ALL mice. In conclusion, this work supports the idea of targeting IgD/FcδR in T-ALL patients with excessive IgD. IgD-Fc-Ig fusion protein might be a potential biological drug with high selectivity for T-ALL treatment.

High serum immunoglobulin D levels in systemic lupus erythematosus: more to be found?

INTRODUCTION: Many studies have shown that serum immunoglobulin D (IgD) is usually increased in autoimmune diseases. The potential role of IgD in systemic lupus erythematosus (SLE) is still unclear. Our study aimed to compare the serum IgD levels of SLE with different population and to evaluate the relationship between serum IgD and SLE. METHODS: Fifty SLE patients, 40 non-SLE chronic kidney disease (CKD) patients, and 50 healthy volunteers were enrolled in this study. Serum IgD levels were analyzed by ELISA assay and compared between groups. The correlation of serum IgD and SLE disease were evaluated. The ability of serum IgD to predict SLE was analyzed by graphing receiver operating characteristic curves. RESULTS: Serum IgD levels were significantly higher in SLE patients compared to non-SLE CKD and healthy controls (7436.1 ± 5862.1 vs. 4517.8 ± 5255.2 vs. 4180.4 ± 4881 ng/mL, p = 0.01, p = 0.002, respectively), and in patients with high SLE Disease Activity Index (SLEDAI) scores compared with those with low scores (8572.9 ± 5968.7 vs. 5020.4 ± 4972.5 ng/mL, p = 0.044). High level of inflammatory cytokines and decreased circulating basophil counts were found in SLE patients (p < 0.05). No correlations was identified between serum IgD levels and SLEDAI scores (p > 0.05). Serum IgD was noninferior to IgG or IgE in discriminating SLE with an area under the curve of 0.672 (95% CI, 0.59-0.75). CONCLUSIONS: Serum IgD levels are significantly elevated in SLE patients with high SLEDAI scores. Simultaneous occurrence of increased inflammatory cytokines and decreased basophil counts highlights the potential role of IgD-targets interaction in SLE pathogenesis. Key points • Total serum IgD levels were elevated in SLE patients. • High IgD levels were significantly higher in SLE patients with high SLEDAI scores. • The ability of serum IgD was equivalent to IgG or IgE in discriminating SLE from CKD and healthy adult.

Multiple Myeloma With a Rare Presentation at Preserved Uninvolved Immunoglobulins.

Multiple myeloma is a neoplastic disease of plasma cells that produces monoclonal immunoglobulins, known as monoclonal proteins, causing hypercalcemia, anemia, renal insufficiency, bone lesion, and other organ damage. In most multiple myeloma, the amount of monoclonal protein correlates with the tumor burden and reflects its prognosis. Uninvolved immunoglobulins are often suppressed as monoclonal protein levels increase as a result of the increasing percentage of myeloma cells in the bone marrow. Detection of monoclonal protein by protein electrophoresis, immunofixation, and serum-free light chain assay is a highly sensitive analysis and is not suitable as a screening test because it is positive in a few percent of healthy elderly people, the majority of whom are classified as benign monoclonal gammopathy of undetermined significance. Therefore, it is widely used in practice to measure quantitation of immunoglobulins by nephelometer, and only when uninvolved immunoglobulins are decreasing in the values for each subtype, monoclonal protein identification by immunofixation, serum-free light chain assay, and bone marrow examination must be additionally performed for proactively diagnosing multiple myeloma. However, we experienced symptomatic multiple myeloma in which uninvolved immunoglobulins were not suppressed and there were no significant changes in immunoglobulin levels despite the relatively rapid progression. It would suggest that if you suspect symptomatic myeloma, you should not rule out the possibility of multiple myeloma because of preserved uninvolved immunoglobulins in laboratory findings.

Immunoglobulin D Multiple Myeloma: A Rare Variant.

Immunoglobulin D multiple myeloma (IgD MM) is a rare isotype of multiple myeloma (MM), comprising less than 2% of all cases. It is often associated with advanced disease at the time of diagnosis, an aggressive clinical course, and shorter overall survival (OS) than other subtypes of MM. There is an increased frequency of undetectable or small monoclonal (M-) protein levels on electrophoresis, hypercalcemia, anemia, lytic bony lesions, and renal failure. However, given the rarity of the disease, there are few cases of IgD MM described in the literature. Given the very small amount of IgD immunoglobulins, they may form very small or undetectable M spike on electrophoresis, making the diagnostic error in diagnosing this specific subgroup very easy. Treatment for MM has seen significant advancement, especially over the last decade, with the advent of medications such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. It is important to understand how IgD MM responds to these newer agents and why this disease continues to be associated with poor outcomes despite advancements in treatment. Small clinical studies on patients with IgD MM show better outcomes following a combination of high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) compared to standard chemotherapy. Given the rarity of the disease, there are no large studies done to see the effectiveness of these treatments, and most of the data are derived from small case series. We report a case of IgD kappa MM that was incidentally discovered following a traumatic bicycle accident. The patient started treatment with bortezomib and dexamethasone (Vd) as an inpatient while he was in the rehabilitation unit and was later switched to bortezomib, dexamethasone, and lenalidomide (VRd) as an outpatient. He has now completed seven cycles and successfully underwent autologous hematopoietic stem cell transplantation.

An IgD-Fc-Ig fusion protein restrains the activation of T and B cells by inhibiting IgD-IgDR-Lck signaling in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and the destruction of small joints. Emerging evidence shows that immunoglobulin D (IgD) stimulation induces T-cell activation, which may contribute to diseases pathogenesis in RA. In this study, we investigated the downstream signaling pathways by which IgD activated T cells as well as the possible role of IgD in the T-B interaction. Peripheral blood mononuclear cells were isolated from peripheral blood of healthy controls and RA patients. We demonstrated that IgD activated T cells through IgD receptor (IgDR)-lymphocyte-specific protein tyrosine kinase (Lck)-zeta-associated protein 70 (ZAP70)/phosphatidylinositol 3-kinase (PI3K)/nuclear factor kappa-B (NF-κB) signaling pathways; IgD-induced CD4+ T cells promoted the proliferation of CD19+ B cells in RA patients. A novel fusion protein IgD-Fc-Ig (composed of human IgD-Fc domain and IgG1 Fc domain, which specifically blocked the IgD-IgDR binding) inhibited the coexpression of IgDR and phosphorylated Lck (p-Lck) and the expression levels of p-Lck, p-ZAP70, p-PI3K on CD4+ T cells, and decreased NF-κB nuclear translocation in Jurkat cells. Meanwhile, IgD-Fc-Ig downregulated the expression levels of CD40L on CD4+ T cells as well as CD40, CD86 on CD19+ B cells in RA patients and healthy controls. It also decreased the expression levels of CD40L on CD4+ T cells and CD40 on CD19+ B cells from spleens of collagen-induced arthritis (CIA) mice and reduced IL-17A level in mouse serum. Moreover, administration of IgD-Fc-Ig (1.625-13 mg/kg, iv, twice a week for 4 weeks) in CIA mice dose-dependently decreased the protein expression levels of CD40, CD40L, and IgD in spleens. IgD-Fc-Ig restrains T-cell activation through inhibiting IgD-IgDR-Lck-ZAP70-PI3K-NF-κB signaling, thus inhibiting B-cell activation. Our data provide experimental evidences for application of IgD-Fc-Ig as a highly selective T cell-targeting treatment for RA.

Therapeutic effect and prognostic influencing factors of IgD multiple myeloma in the new immunotherapy era / 白血病·淋巴瘤

Objective:To investigate the clinical characteristics, efficacy and prognostic influencing factors of IgD multiple myeloma (MM) in the new immunotherapy era.Methods:The clinical data of 29 patients diagnosed with IgD MM in the Affiliated Hospital of Xuzhou Medical University from March 2014 to February 2021 were retrospectively collected. The clinical characteristics, treatment regimens and efficacy, especially the efficacy of new drugs and immunotherapy for the disease were analyzed. Kaplan-Meier method was used to analyze the overall survival (OS) and progression-free survival (PFS). Multivariate Cox proportional risk model was used for analysis of prognostic influencing factors.Results:The median age of patients was 58 years. There were 20 cases (69.0%) below 65 years, 12 cases (41.4%) of complicated with stomach function damage, 6 cases (20.7%) of extramedullary invasion. All patients were treated with combined therapy containing proteasome inhibitor bortezomib in the first-line therapy, and the overall response rate was 82.8% (24/29). Among 21 relapsed/refractory patients, 12 patients were treated with the second-line or above treatment regimen chimeric antigen receptor T cell (CAR-T) immunotherapy, including 9 cases achieving very good partial remission (VGPR) or above; 5 patients were treated with the new drug daratozumab, including 1 case achieving complete remission (CR). The median OS time of 29 patients was 48 months (95% CI 17-79 months), the median PFS time after the first-line treatment was 9 months (95% CI 3-15 months), and the median PFS time after the second-line treatment was 11 months (95% CI 1-21 months). Multivariate Cox regression results showed that CAR-T therapy is an independent influencing factor of the prognosis of relapsed/ refractory IgD MM patients ( HR = 0.094, 95% CI 0.019-0.473, P = 0.004). Conclusions:IgD MM patients are characterized with lower onset age, more renal function damage and a high incidence of extramedullary invasion. The first-line therapy containing proteasome inhibitor has a better short-term efficacy, and CAR-T therapy can improve the remission rate and survival rate of relapsed/refractory IgD MM to a certain extent.

IgD promotes pannus formation by activating Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in FLS of CIA rats and the regulation of IgD-Fc-Ig fusion protein.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation, synovial hyperplasia, cartilage degeneration, bone erosion, and pannus. Immunoglobulin D (IgD) plays an important role in autoimmune diseases although the content of it in vivo is low. Increased concentrations of anti-IgD autoantibodies have been detected in many RA patients. IgD-Fc-Ig fusion protein is constructed by connecting human IgD Fc domain and IgG1 Fc domain, which specifically block the IgD/ IgDR pathway and regulate the function of cells expressing IgDR to treat RA. The expression levels of Wnt5A and Frizzled 5 are higher in RA synovial tissue specimens. The complex of Wnt5A-Fzd5-LRP5/6-CTHRC1 promotes the expression of hypoxia inducible factor-1α by activating nuclear factor kappa-B (NF-κB), leading to high expression of VEGF and participating in angiogenesis. VEGF is the strongest angiogenic factor found so far. Here, we aimed to explore whether IgD participates in synovitis by binding to IgDR and regulating the activation of Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in fibroblast synovial cells (FLSs), whether IgD-Fc-Ig fusion protein inhibits VEGF production in FLS of CIA and explore mechanism. We found that IgDR is expressed on MH7A and FLS. IgD promotes VEGF expression by activating Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in MH7A and FLS. After activation of Fzd5 with Wnt5A, IgD-Fc-Ig reduced VEGF-A level in the culture supernatant of MH7A stimulation by IgD. The expressions of CTHRC1, Fzd5, p-P65 and VEGF in MH7A and FLSs were down-regulated after IgD-Fc-Ig treatment. IgD-Fc-Ig suppressed the combination of CTHRC1 and Fzd5 as well. By using the animal model, we demonstrated that IgD-Fc-Ig suppress ankle CTHRC1 and Fzd5 production resulted in inhibition of index of joint inflammation of CIA rats, which were consistent with vitro results. Conclusively, IgD-Fc-Ig inhibits IgD and Wnt5A-induced angiogenesis and joint inflammation by suppressing the combination of CTHRC1 and Fzd5. Our results show that IgD-Fc-Ig exerts its suppressive effect on IgD and Wnt5A by Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway.

Immunoglobulin D-λ/λ biclonal multiple myeloma: A case report.

BACKGROUND: Immunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of MM and commonly occurs in younger subjects but at a later stage of the International Staging System (ISS) when admitted. As a special type of IgD myeloma, IgD-λ/λ biclonal MM is rarer. Its serum protein electrophoresis and serum immuno-fixation electrophoresis (IFE) might find no anomalies even if the bone marrow (BM) examination is performed. Thus, it is easy to miss the diagnosis. CASE SUMMARY: A 62-year-old man diagnosed as IgD-λ/λ myeloma (ISS stage III) was admitted with fatigue and weight loss. The physical examination suggested an anemic face, a few moist rales at the left lung base, and mild concave edema in both lower extremities. Laboratory examinations showed the elevated creatinine levels, ß2-microglobulin, lactic dehydrogenase, and erythrocyte sedimentation rate, while the decreased neutrophils, granulocytes, and hemoglobin. In the serum protein electrophoresis, there appeared two inconspicuous M-spikes. Serum IFE indicated an over-representation of lambda light chain and yielded two monoclonal bands in λ region, but only one corresponding heavy chain band in the antisera to IgD region. The BM histology and BM cytology both supported the diagnosis of IgD-λ/λ myeloma. CONCLUSION: This case highlights the differential clinical manifestations and laboratory findings of IgD-λ/λ myeloma to help minimize the chance of misdiagnosis.

Efficacy and Safety of Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Immunoglobulin D Multiple Myeloma.

Immunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of MM that carries a worse prognosis than non-IgD subtypes. Compared with non-IgD subtypes, IgD MM is associated with a shorter survival time. The application of chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory multiple myeloma (R/R MM) has increasing evidence as an efficacious treatment. This study was designed to investigate efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory IgD MM (R/R IgD MM). In this single-arm, phase 2 trial, patients diagnosed with R/R IgD MM were infused with either a combination of anti-B-cell maturation antigen and anti-CD19 CAR T-cells or anti-CD19 CAR T-cells alone, with subsequent evaluation of therapeutic response and treatment-related toxicities. At the data cutoff date, 7 patients were enrolled in our study, and all patients achieved response based on the International Myeloma Working Group Uniform Response Criteria. Six patients achieved stringent complete remission (sCR) within 60 days after CAR T-cell infusion (median time 58 days, range 18 to 90 days), and 1 patient with extramedullary disease achieved minimal response (MR) at 30 days after infusion. Bone marrow minimal residual disease (MRD) negativity was achieved in all patients, and the median time to achieve MRD negativity was 22 days (range 14 to 60 days). The most common grade 3 to 4 treatment-related toxicities were hematological toxicities. All patients experienced cytokine release syndrome (CRS), although CAR T-cell-related neurotoxicity was not observed. In our study, CAR T-cell therapy showed encouraging efficacy in the patients with R/R IgD MM, achieving high rates of sCR and MRD negativity. Aside from CRS and prolonged hematologic toxicities, other adverse reactions were mild, suggesting that this is a well-tolerated treatment with a high therapeutic potential.

Immunoglobulin D-kappa multiple myeloma in a patient with rheumatoid arthritis: a case report and review of the literature.

A 77-year-old Japanese woman with a 21-year history of seropositive, erosive rheumatoid arthritis (RA) and a 10-year history of methotrexate (MTX) therapy was admitted with malaise and mild consciousness disturbance. Laboratory data showed hypercalcemia, acute kidney injury, normocytic anaemia, and thrombocytopenia. As we first assumed drug-induced toxicity by MTX and eldecalcitol, both were discontinued and leucovorin rescue therapy and calcitonin were administered. However, her condition continued to worsen. Serum protein electrophoresis showed only a small M-peak, immunoelectrophoresis of both the serum and urine demonstrated Bence-Jones kappa (κ) type monoclonal protein without immunoglobulin heavy chain, and bone marrow examination revealed proliferation of plasma cells. We diagnosed her with Bence-Jones κ type multiple myeloma (MM) and transferred her to the department of haematology of a higher order medical institution. Conclusively, the diagnosis of immunoglobulin (Ig) D-κ type MM, a rare variant of this disorder, was determined in accordance with serum immunofixation. Several previous studies have suggested that pre-existing RA is a risk factor for MM. Although IgD MM is characterised by its clinical severity and poor prognosis compared to other subtypes, it is often misdiagnosed or mistaken as light chain type MM, as in the present case, because of the low level of IgD M-protein, resulting in delayed diagnosis. Physicians must take MM into consideration as a differential diagnosis when inactive RA patients present with inexplicable elevated calcium, renal failure, anaemia, and bone lesion symptoms and should be aware of IgD MM to establish the correct diagnosis promptly.

Four immunoglobulin isotypes and IgD splice variants in urodele amphibians.

Until recently, different families of urodele amphibians were thought to express distinct subsets of immunoglobulin (Ig) isotypes. In this study, we explored cDNAs encoding Ig heavy-chains (H-chains) in three species of urodele amphibians. We found that Cynops pyrrhogaster, Pleurodeles waltl, and Ambystoma mexicanum each carry genes encoding four Ig H-chain isotypes, including IgM, IgY, IgD, and IgX, similar to those found in anuran amphibians. We also found that urodele IgDs have a long constant region similar to those found in anuran, reptiles, and bony fishes. We also found several putative IgD splice variants. Our findings indicated that P. waltl IgP is not a novel isotype but an IgD splice variant. Altogether, our findings indicate that IgD splice variants may be universally expressed among amphibian species.

Síndrome de Hiper IgD: espectros clínicos, achados genéticos e condutas terapêuticas / Hyper-IgD syndrome: clinical spectrum, genetic findings, and therapeutic approaches

A deficiência de mevalonato quinase (MVK; MIM #142680; ORPHA #343) é uma doença genética, espectral, rara, associadas a mutações ao longo do gene MVK causando distúrbios na síntese do colesterol, que culminam em: inflamação sistêmica com febre, adenopatia, sintomas abdominais e outros achados clínicos. Enquanto no polo leve da doença os achados mais comuns são febres recorrentes com linfadenopatia, no polo mais grave adiciona-se o acometimento do sistema nervoso central (meningites assépticas, vasculites e atraso do desenvolvimento neuropsicomotor) e do sistema hematopoiético (síndrome de ativação macrofágica). Apesar de inúmeras terapêuticas, os bloqueadores da interleucina-1 ainda são os únicos medicamentos capazes de controlar a doença e de impedir a evolução para amiloidose. Os estudos atuais visam tentar novos tratamentos, como o transplante de células-tronco hematopoiéticas, ou mesmo a terapia gênica.

Mevalonate kinase deficiency (MVK; MIM #142680; ORPHA #343) is a rare spectral genetic disorder linked to mutations along the MVK gene leading to impaired cholesterol synthesis, clinically observed as systemic inflammation with fever, adenopathy, abdominal manifestations, and other clinical findings. While on mild forms recurrent fever with lymphadenopathy is commonly observed, severe forms add to that neurological (aseptic meningitis, vasculitis, and neuropsychomotor developmental delay) and hematopoietic involvement (macrophage activation syndrome). Despite of several therapeutic approaches, blocking interleukin-1 is the only effective method to control the disease and prevent the development of systemic amyloidosis. Ongoing studies aim to test new treatments, such as hematopoietic stem cell transplantation and gene therapy.

Regulation of T Cell Activities in Rheumatoid Arthritis by the Novel Fusion Protein IgD-Fc-Ig.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and T cell hyper-activation. Emerging evidence has shown that the stimulation of immunoglobulin D (IgD) induces T cell activation and may contribute to disease pathogenesis. In this study, the sIgD concentrations were positively associated with disease activity score in 28 joints (DAS28) and anti-cyclic citrullinated peptide (anti-CCP) in RA. We demonstrated that IgD-Fc-Ig (composed of human IgD Fc domain and IgG1 Fc domain, obtained through prokaryotic protein expression and chromatography purification) effectively inhibited the activation and proliferation of T cells in healthy controls and PBMCs in RA patients stimulated by IgD, recovered the Th17/Treg cell subset balance, and downregulated p-Lck and p-ZAP70 expression. Moreover, in vivo, IgD-Fc-Ig decreased the swollen joint counts and arthritis indices in mice with collagen-induced arthritis (CIA), and ameliorated histopathological changes in joint and spleen tissue. It also downregulated thymocyte proliferation and reduced the percentage of helper T cells (Th) and CD154+ T cells, reversed the imbalance of Th1/Th2 and Th17/Treg cell subsets, reduced cytokine and chemokine levels, and inhibited p-Lck and p-ZAP70 expression. Our data suggest that IgD-Fc-Ig fusion protein regulates T cell activity in RA. These findings have potential implications for IgD-targeted strategies to treat IgD-associated RA.

Immunoglobulin D (IgD) and IgD receptor expression in diffuse large B-cell lymphoma.

Objective: Immunoglobulin D (IgD) levels are often elevated in patients with autoimmune diseases. However, the oncogenic activities of IgD and IgD receptor (IgDR) in diffuse large B-cell lymphoma (DLBCL) have not been reported in detail. Therefore, we aimed to investigate the expression of IgD and IgDR in patients with DLBCL. Methods: Membrane IgD (mIgD) and IgDR expression in tissue samples was analyzed using IHC, mIgD and IgDR expression on peripheral blood mononuclear cells (PBMCs) was analyzed by FCM, and secreted IgD (sIgD) level was analyzed by ELISA. Fisher's exact test and Spearman correlation analysis were used to evaluate the relationship between IgD, IgDR, and clinical parameters. Results: The pathological lymph nodes of 34 patients with DLBCL were studied, and mIgD and IgDR expression was found in 16 and 19 patients. mIgD and IgDR expression was upregulated in patients with DLBCL and mIgD expression was significantly associated with IgDR expression. Further correlation analysis showed that mIgD expression was correlated with serum ß2-MG level and Hans algorithm as germinal center B (GCB), whereas IgDR expression correlated with serum LDH level, IPI score and GCB. ELISA showed that sIgD level was significantly increased in DLBCL patients and it correlated with serum ß2-MG and LDH levels. FCM showed that mIgD and IgDR expression in PBMCs of patients with DLBCL was significantly higher than that in healthy controls. Conclusion: Our findings suggest that overexpression of IgD and IgDR is an abnormal activation state in DLBCL.

Clinical characteristics and prognosis of immunoglobulin D myeloma in the novel agent era.

Immunoglobulin D (IgD) myeloma is a rare subtype that used to lead to a poor outcome. To investigate the current clinical features, cytogenetic changes and survival of patients with IgD myeloma under novel treatments, we analysed 47 patients with IgD myeloma, 31 men and 16 women, with a median age of 54.5 years. We found that IgD myeloma was associated with higher frequencies of anaemia, renal failure, and hypercalcemia and higher levels of serum LDH compared with non-IgD myeloma. More than 90% of patients with IgD myeloma had at least one cytogenetic abnormality demonstrated by fluorescence in situ hybridisation (FISH). IGH translocations were the most common abnormalities, which were mainly caused by t(11;14). Moreover, 36.2% of patients were at the Revised International Staging System (RISS) stage III when diagnosed. Those patients had significantly shorter PFS and OS compared with patients at RISS stages I and II. In conclusion, IgD myeloma has specific clinical characteristics. The RISS grade was shown to be a simple and effective method to predict the prognosis of patients with IgD myeloma.

Local regulation of immune genes in rainbow trout (Oncorhynchus mykiss) naturally infected with Flavobacterium psychrophilum.

Flavobacterium psychrophilum is the etiological agent of bacterial cold water disease (BCWD), also referred to as rainbow trout fry syndrome (RTFS), a disease with great economic impact in salmonid aquaculture. Despite this, to date, not many studies have analyzed in depth how the immune system is regulated during the course of the disease. In the current study, we have studied the transcription of several immune genes related to T and B cell activity in the skin of rainbow trout (Oncorhynchus mykiss) naturally infected with F. psychrophilum in a farm located in Lake Titicaca (Peru). The levels of expression of these genes were tested and compared to those obtained in asymptomatic and apparently healthy rainbow trout. In the case of symptomatic fish, skin samples containing characteristic ulcerative lesions were taken, as well as skin samples with no lesions. Our results pointed to a significant local up-regulation of IgD, CD4, CD8, perforin and IFNγ within the ulcerative lesions. On the other hand, no differences between the levels of expression of these genes were visible in the spleen. To confirm these results, the distribution of IgD+ and CD3+ cells was studied through immunohistochemical techniques in the ulcerative lesions. Our results demonstrate a strong local response to F. psychrophilum in rainbow trout in which IgD and T cells seem to play a major role.