Hypersensitivity to mosquito bites: A versatile Epstein-Barr virus disease with allergy, inflammation, and malignancy.

Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by transient intense skin reaction and systemic inflammation. Clinical presentation of HMB resembles other mosquito allergic responses, and it can also be difficult to clinically distinguish HMB from other severe allergic reactions. However, a distinctive pathophysiology underlies HMB. HMB belongs to a category of Epstein-Barr virus (EBV)-associated natural killer (NK) cell lymphoproliferative disorders (LPD). Hence, HMB may progress to systemic diseases, such as hemophagocytic lymphohistiocytosis, chronic active EBV disease, and EBV-associated malignancies. A triad of elevated serum IgE, NK lymphocytosis, and detection of EBV DNA in peripheral blood is commonly observed, and identification of EBV-infected NK cells usually facilitates the diagnosis. However, the effective treatment is limited, and its precise etiology remains unknown. Local CD4+ T cell proliferation triggered by mosquito bites appears to help induce EBV reactivation and EBV-infected NK-cell proliferation. These immunological interactions may explain the transient HMB signs and symptoms and the disease progression toward malignant LPD. Further research to elucidate the mechanism of HMB is warranted for better diagnosis and treatment of HMB and other forms of EBV-associated LPD.

[30 Years of the Tragedy in Chernobyl. Clinical and Immunological Effects in Liquidators of Consequences of the Chernobyl Accident. Main Results of Long-Term Monitoring].

Results of long-term immunological monitoring of liquidators of consequences of the Chernobyl accident and the revealed regularities are presented. Earlier the unknown phenomenon of the activating influence of radiation at small doses on the T-cellular link of the immune status (IS), mainly on T-lymphocytes/helper was for the first time established. This phenomenon came to light among participants of LPA working in an extreme situation of 1986 in the zones of the CN PP and further was confirmed by inspection of the personnel of a 30-km zone of the CNPP in 1990; the personnel at radiation dangerous nuclear power plants and the population living near these objects, the population polluted by radionuclides on the territories of the Bryansk region. This effect in the presence of clinical symptoms which can be caused by influence of a radiation factor was most expressed. Prognostic value of the changes in the development of IS immune insufficiency (ID), cellular and humoral link in the near future after taking part in clean-up workers are established. These laws have a theoretical value for immunology and radiobiology, and practical health care as well, as the formation of a phenotype of IS defines approaches to immunoprophylactics and immunocorrection, as in extreme situations, and in the following years. During the delayed periods development of an imbalance, immune in- sufficiency in T-lymphocytes and natural killer cells is revealed. By the end of the 3rd - the beginning of the 4th fifth anniversary after the accident the high frequency of clinical manifestations of immune dysfunction and chronic somatic diseases was defined. The immunological characteristic of an immunoproliferative syn- drome that allowed one to reveal predictors of early diagnostics of malignant new growths in immune status is for the first time established. Clinical-immunological signs of early aging of liquidators and features of changes in liquidators in the lipidic status depending on the age and risk factors of Chernobyl accident are revealed. Features of antiviral protection of an organism ofliquidators that is defined by changes in the cluster of genes of cytokines (IL28A, IL28B and IL29) localized on the 19th chromosome (19ql3) of the person are established. Establishment of genotypes can be associated with a positive effect of treatment, steady and long remission of GVI.

Intravenous Immunoglobulin G Improves Pregnancy Outcome in Women with Recurrent Pregnancy Losses with Cellular Immune Abnormalities.

PROBLEM: We investigated the therapeutic effect of intravenous immunoglobulin (IVIG) in women with recurrent pregnancy loss (RPL). METHOD OF STUDY: This was a retrospective observational study. Total 189 RPL women who experienced ≥2 miscarriages were enrolled and investigated conventional etiologies, thrombophilia, and cellular immunity. Patients were divided into four groups; known etiology with (Gr1) and without cellular immune abnormality (Gr2), unknown etiology with (Gr3) and without cellular immune abnormality (Gr4). IVIG was administrated from early pregnancy to 30 weeks of gestation to women with cellular immune abnormality (Gr1 + Gr3). RESULTS: Cellular immune abnormalities (increased level or cytotoxicity of NK cells and Th1/Th2 ratio) were present in 111 of 189 RPL women (58.7%). Live birth rates of women with and without cellular immune abnormality were not different (Gr1 + Gr3, 84.8% versus Gr2 + Gr4, 89.7%). Furthermore, IVIG success rates were the same between Gr1 and Gr3, those who had cellular immune abnormality. Nevertheless lack of an appropriate control in this study, our IVIG outcome demonstrated better live birth rate compared with those of other investigators. CONCLUSION: Treatment modalities stratified by underlying etiologies of RPL may improve pregnancy outcome. Administration of IVIG is likely to have clinical efficacy in RPL women with cellular immune abnormality.

Altered lymphopoiesis and immunodeficiency in miR-142 null mice.

MicroRNAs (miRNAs) are a class of powerful posttranscriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with a targeted deletion of this gene. Our analysis of miR-142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, whereas the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of B-cell-activating factor (BAFF) receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B-cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B-cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis, and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.

Utility of immunologic testing in suspected rheumatologic disease.

The use of diagnostic testing in the clinical practice of medicine has been a shifting landscape from the time that the first blood test was utilized. This is no different in the field of immunology and in particular rheumatology. As the field of immunology is relatively young, the clinical tests are not well established and therefore guidelines for use are still under debate. In this review, we seek to look at some of the key autoantibodies, as well as other tests that are available to diagnose suspected rheumatologic disease, and examine how to best use these tests in the clinic. In particular, we will focus on the anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, complement, cryoglobulins, rheumatoid factor, and anti-citrullinated protein antibodies.

Hydroxy-itraconazole pharmacokinetics is similar to that of itraconazole in immunocompromised patients receiving oral solution of itraconazole.

BACKGROUND: The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole (ITZ), is not fully known. METHODS: Oral solution of ITZ was administered in 46 immunocompromised patients as a single 200 mg dose for at least 12 days. The plasma concentrations of ITZ, active OH-ITZ, and keto-itraconazole (keto-ITZ), an inactive metabolite, 12 h after administration were determined by LC-UV or LC-MS/MS. RESULTS: The mean±SD of plasma concentrations of ITZ, OH-ITZ, and keto-ITZ were 833±468, 798±454, and 3.94±2.68 µg/l, respectively. A greater correlation coefficient was observed between plasma concentrations of ITZ and OH-ITZ (r=0.90, P<0.01) than between OH-ITZ and keto-ITZ (r=0.44, P<0.01). Plasma concentration of OH-ITZ was inversely correlated with concentration ratio of keto-ITZ to OH-ITZ (r=-0.52, P<0.01). Plasma concentrations of ITZ and OH-ITZ were correlated with serum concentration of albumin (r=0.36, P=0.01 and r=0.37, P=0.01) and estimated glomerular filtration rate (r=-0.27, P=0.08 and r=-0.35, P=0.02). CONCLUSIONS: The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-ITZ, serum concentration of albumin, and renal function in immunocompromised patients. The plasma concentration of OH-ITZ was strongly correlated with that of ITZ. Prevention of fungal infections can be improved by determining the plasma concentration of ITZ or OH-ITZ.

CD200 expression in plasma cells of nonmyeloma immunoproliferative disorders: clinicopathologic features and comparison with plasma cell myeloma.

The majority of plasma cell myelomas (PCMs) are positive for CD200, a membrane protein with immunosuppressive function. There are no flow cytometry data in the literature on plasma cell CD200 expression in other immunoproliferative disorders. Therefore we used flow cytometry to study the expression of CD200 on plasma cells in diagnostic bone marrow aspirates from 61 patients with monoclonal gammopathy of undetermined significance (MGUS) and 10 patients with lymphoplasmacytic lymphoma (LPL). For comparison, we evaluated CD200 expression in 74 PCM bone marrow biopsies. Thirty-three (54.1%) of 61 MGUS cases and 2 (20.0%) of 10 LPL cases were CD200+. Comparative clinicopathologic parameters for MGUS cases, based on CD200 expression status, showed no differences between the 2 groups. The proportion of CD200+ PCMs (73.0%) in our series was significantly higher than that of CD200+ MGUS (P = .030) and CD200+ LPL (P = .002) cases.

Morphologic features of extrahepatic manifestations of hepatitis C virus infection.

Cirrhosis and hepatocellular carcinoma are the prototypic complications of chronic hepatitis C virus infection in the liver. However, hepatitis C virus also affects a variety of other organs that may lead to significant morbidity and mortality. Extrahepatic manifestations of hepatitis C infection include a multitude of disease processes affecting the small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system. The majority of these conditions are thought to be immune mediated. The most documented of these entities is mixed cryoglobulinemia. Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney. Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis. This paper highlights the histomorphologic features of these processes, which are typically characterized by chronic inflammation, immune complex deposition, and immunoproliferative disease in the affected organ.

Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.

Somatic gain-of-function mutations in members of the RAS subfamily of small guanosine triphosphatases are found in > 30% of all human cancers. We recently described a syndrome of chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity associated with a mutation in NRAS affecting hematopoietic cells, and initially we classified the disease as a variant of the autoimmune lymphoproliferative syndrome. Here, we demonstrate that somatic mutations in the related KRAS gene can also be associated with a nonmalignant syndrome of autoimmunity and breakdown of leukocyte homeostasis. The activating KRAS mutation impaired cytokine withdrawal-induced T-cell apoptosis through the suppression of the proapoptotic protein BCL-2 interacting mediator of cell death and facilitated proliferation through p27(kip1) down-regulation. These defects could be corrected in vitro by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 or phosphatidyl inositol-3 kinase inhibition. We suggest the use of the term RAS-associated autoimmune leukoproliferative disease to differentiate this disorder from autoimmune lymphoproliferative syndrome.

[Angiocentric T-cell lymphoma of the lung]. / A tüdö angiocentrikus t-sejtes lymphomája.

Angiocentric T-cell lymphoma of the lung. The case history of a patient with primary angiocentric T-cell lymphoma of the lung having an unusually long survival period (> 10 years) is presented. Attention is paid to the possibilities of differential diagnosis that should be taken into account in the analysis of certain lymphocytic infiltrates of the lung. In accordance with relevant data of the literature, this case shows that pleiomorphic small cell T-lymphomas may have a protracted course, and the disease free periods repeatedly achieved in this patient by irradiation and chemotherapy are thought to be noticeable. Authors refer to some recent findings which may give new insights in the pathobiology of extranodal T-cell lymphomas, and result in recognition of new disease entities.

Spindle cell tumor of lymph node of probable reticulum cell origin associated with multiclonal gammopathy.

We describe a case of a 48 year old man who presented repeatedly with a neck lymph node tumor. The tumor grew insidiously over 11 years and the patient died at the age of 58 with the generalization of the tumor into the right cervical, paratracheal lymph nodes and spleen. The tumor was composed of spindle shaped cells with occasional intranuclear cytoplasmic pseudoinclusion. At the ultrastructural level the tumor revealed membrane bound crystalline inclusions, which were locally in direct contact with both the nuclear envelope and confronting cisternae of the endoplasmic reticulum. The tumor was associated with multiclonal gammopathy composed of two subsets of IgG/lambda and one subset of IgA/lambda positive paraprotein produced by lymphoid cells surrounding the tumor. We diagnosed the tumor as "spindle cell tumor of lymph node of probable reticulum cell origin associated with multiclonal gammopathy" and consider the lymphoid tissue producing the paraprotein to be reactive.

Role of cytokines in the pathogenesis of monoclonal gammopathies.

OBJECTIVE: To review data that postulate a role for cytokines and oncogenes in the pathogenesis of monoclonal gammopathies. DESIGN: Published studies that provide evidence of the clinical progression of normal B cells to monoclonal gammopathy of undetermined significance (MGUS) to active myeloma are discussed. RESULTS: On the basis of mouse plasmacytoma models, increased expression of c-myc in B lymphocytes may be the initial oncogenic event that leads to MGUS in humans. Over time, this monoclonal subpopulation may acquire additional genetic abnormalities, such as aberrant interleukin (IL) 1 beta expression. Because IL 1 beta has potent osteoclast activating factor activity, increased production of IL 1 beta by monoclonal plasma cells may be the genetic event responsible for the progression of MGUS to myeloma. The in vivo plasma cell labeling index (proliferative rate) is the most powerful prognostic factor in patients with myeloma. The proliferative compartment observed in myeloma may parallel normal B-cell development because cytoplasmic immunoglobulin-positive cells with the ability to proliferate exist normally. With continued progression of disease, the ratio of proliferating monoclonal plasmablasts to nonproliferating monoclonal plasma cells may increase under the influence of cytokines such as IL 6. CONCLUSION: A more complete understanding of the basic biologic features of myeloma should lead to innovative therapies in the future.

Angiocentric immunoproliferative lesions: a molecular analysis of eight cases.

Angiocentric immunoproliferative lesions (AILs) are believed to represent a unique type of extranodal malignant lymphoma on the basis of clinicopathologic and immunophenotypic evidence. However, molecular studies to assess clonality have been performed on a small number of cases. In this study we assessed the clonality of eight AILs using restriction fragment analysis, the Southern blot technique, and probes to assess the configuration of the T-cell receptor beta, gamma, and delta chain genes and the immunoglobulin heavy and K light chain genes. In addition, the presence of the Epstein-Barr (EB) viral genome was assessed by using both Southern blot analysis (seven cases) and polymerase chain reaction amplification (five cases). Our results demonstrate that gene rearrangements are rare in AILs. A clonal gene rearrangement was identified in only one case, a grade III AIL with a rearrangement of the T-cell receptor delta chain gene. In two additional AILs (both grade III), the EB viral genome was detected as a single band by Southern blot analysis with a probe derived from the terminal repeat region of the virus, suggesting that a single episomal configuration of the EB viral genome was present in each case, as would occur in a clonal population of infected cells. In the remaining cases there was no evidence of clonality, although EB sequences were detected in one of four cases using the polymerase chain reaction. The rarity or absence of gene rearrangements in AILs is difficult to explain if AILs are malignant, presumably monoclonal lymphomas. However, their frequent association with the EB virus may suggest an analogy between AILs and lymphoproliferative disorders that occur in immunosuppressed patients. These findings further emphasize the unique clinicopathologic aspects of AILs and may also be useful diagnostically in the differential diagnosis of lymphoproliferative disorders.

Serum IgG from an autoimmune prone mouse C3H/HeJ-gld/gld supports the interleukin-3-dependent cell line through an autocrine mechanism.

C3H/HeJ-gld/gld(C3H/gld) mice have been shown to develop massive lymphadenopathy with autoimmunity. In this study, we tested whether C3H/gld-IgG supports the growth of the IL-3-dependent cell line, FDC-P2/185-4. Serum IgG from C3H/gld mice stimulated FDC-P2/185-4 cells to proliferate. On the other hand, IgG from C3H/HeJ-+/+ did not show such activity. This activity increased with age in both sexes of C3H/gld mice. It was suggested that a monomeric IgG component was responsible for the proliferative activity of C3H/gld mouse sera. The cell-induced growth required Fc gamma receptors on FDC-P2/185-4 cells. FDC-P2/185-4 cells stimulated with C3H/gld-IgG, secreted IL-3, and grew by themselves, indicating an autocrine mechanism. Thus, cytokines produced by serum IgG may play an important role in the development of disease in mice bearing the autosomal recessive mutation gld.

Multivisceral intestinal transplantation: surgical pathology.

We report the diagnostic surgical pathology of two children who underwent multivisceral abdominal transplantation and survived for 1 month and 6 months. There is little relevant literature, and diagnostic criteria for the various clinical possibilities are not established; this is made more complicated by the simultaneous occurrence of more than one process. We based our interpretations on conventional histology, augmented with immunohistology, including HLA staining that distinguished graft from host cells in situ. In some instances functional analysis of T cells propagated from the same biopsies was available and was used to corroborate morphological interpretations. A wide spectrum of changes was encountered. Graft-versus-host disease, a prime concern before surgery, was not seen. Rejection was severe in 1 patient, not present in the other, and both had evidence of lymphoproliferative disease, which was related to Epstein-Barr virus. Bacterial translocation through the gut wall was also a feature in both children. This paper documents and illustrates the various diagnostic possibilities.

Systemic polyclonal immunoblastic proliferations.

This report describes the clinical and pathologic features of four patients with a florid, systemic immunoblastic proliferation. The blood of these patients exhibited a mild to marked leukocytosis with a high percentage of immunoblasts and plasma cells. The bone marrow also was infiltrated extensively by immunoblasts. Lymph node biopsy specimens from two patients showed near total effacement of the nodal architecture by a diffuse infiltration of immunoblasts and plasma cells. The proliferative process was determined to be polyclonal with immunohistochemical techniques. Cytogenetic studies of bone marrow from two patients showed a pseudodiploid abnormal clone, with a translocation involving a break in band 14q32 in each case. The pathogenesis of these proliferative disorders in unclear, although three patients had some evidence of an acute immune disorder. One of these patients was treated with steroids, vincristine, and cyclophosphamide. Another patient was treated with steroids only, and one patient was treated with steroids and cyclophosphamide. All had rapid regression of the disease process. Two patients are alive and apparently free of disease 31 and 48 months after diagnosis. One died of sepsis. The fourth patient had acquired immune deficiency syndrome (AIDS) and died without therapy. The biology of the immunoblastic proliferation of these patients is uncertain. The immunohistochemical results suggest a reactive, polyclonal proliferation, but the cytogenetic abnormalities in two patients indicate the possibility of a cryptic neoplastic clone.