In utero sensitization modulates IgG isotype,IFN‐γ and IL‐10 responses of neonates in bancroftian filariasis

In utero exposure has been considered as a risk factor for filarial infection. To evaluate the influence of maternal infection on filarial‐specific IgG subclass response in neonates and their correlation with plasma levels IL‐10 and interferon‐γ, 145 pairs of mothers and their respective cord bloods were examined. Transplacental transfer of circulating filarial antigen (CFA) was observed in 34·8% cord bloods from CFA positive mothers. Filarial‐specific IgG1, IgG2 and IgG4 responses of cord bloods were found to be positively correlated with CFA of mothers. In contrast, IgG3 responses negatively correlated with CFA of mothers. The % of similarity of recognition pattern in the cord blood with maternal blood was high for IgG3 response than IgG4 in all three groups. An increased levels of IL‐10 and decreased levels of interferon gamma (IFN‐γ) were observed in cord blood of infected mothers. Interferon gamma was positively correlated with IgG3 and negatively correlated with IgG4 level. On the other hand, IL‐10 was positively correlated with IgG4 and CFA, indicating that cytokines may play a role in modulating the immune responses in cord bloods of sensitized foetus. The findings of the study reveal that in utero tolerance or sensitization may influence the filarial‐specific immunity to infection in neonates.     

Adult worm‐specific IgE/IgG4 balance is associated with low infection levels of Schistosoma mansoni in an endemic area

Field studies have suggested an immune‐mediated mechanism associated with resistance to Schistosoma mansoni infection. Overall, levels of specific IgE have been correlated with resistance to infection, whereas levels of IgG4 have been associated with susceptibility. This study aimed to evaluate serum levels of soluble adult worm antigen preparation (SWAP)‐specific IgE and IgG4 in relation to current infection in a large casuistic of individuals living in an endemic area of schistosomiasis in Bahia, Brazil. The prevalence of S. mansoni infection was 37·7% and the mean parasite burden was 55·4 (0–2100) epg/faeces. There was no significant difference in the levels of SWAP‐specific IgE in individuals with different parasite burden, whereas high producers of parasite‐specific IgG4 presented higher parasite burden when compared to low IgG4 producers. Additionally, S. mansoni parasite load was positively correlated with the levels of specific IgG4 or total IgE. No significant correlation was observed between parasite burden and SWAP‐specific IgE. Nevertheless, SWAP‐specific IgE/IgG4 ratio was higher in uninfected or lightly infected individuals (1–99 epg/faeces) than in heavily infected ones (≥400 epg/feces). These findings highlight the important role of IgE/IgG4 ratio in the resistance to infection, which could be useful for further studies in schistosomiasis vaccine candidates.     

IgG4‐related retroperitoneal fibrosis: a newly characterized disease

Retroperitoneal fibrosis (RPF) is a rare disease characterized by chronic, nonspecific inflammatory and sclerotic or fibrotic tissue in the periaortic or periiliac retroperitoneum that encases adjacent structures. There will be a series of clinical manifestations once the proliferated fibrous tissues encase the abdominal aorta, iliac arteries and urinary duct. RPF is generally divided into two types: idiopathic retroperitoneal fibrosis (IRPF) without identified pathogenesis, making up about two‐thirds of cases, and secondary retroperitoneal fibrosis. Recent studies on Immunoglobulin G4‐related disease (IgG4‐RD) reveal that abundant infiltration of IgG4 positive plasma cells is found in biopsies on the mass of RPF of some IRPF patients, which is identified as one spectrum of IgG4‐RD and is named IgG4‐related RPF. IgG4‐related RPF is often misdiagnosed as retroperitoneal visceral malignancy and is treated with surgery. In addition, because of its good response to glucocorticoid, early detection and treatment is important. We review the definition, epidemiology, clinical features, diagnostic criteria, treatment and prognosis of IgG4‐related RPF in this article to raise awareness of this newly characterized disease.     

IgG4‐related disease and lymphocyte‐variant hypereosinophilic syndrome: A comparative case series

Chronic lymphocytic leukaemia (CLL) is a chronic B‐cell lympho‐proliferative disorder in which lymphomatous transformations occur in 5%‐15% of patients. Histologically these cases resemble diffuse large B‐cell lymphoma, or Richter's transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67‐year‐old female with CLL treated with the novel Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno‐histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.     

IgG4‐related disease with hypergammaglobulinemic hyperviscosity and retinopathy

Immunoglobulin G4‐related disease (IgG4‐RD) is a recently described entity with protean manifestations. We describe a novel case of IgG4‐RD with hypergammaglobulinemic hyperviscosity responsive to fludarabine and rituximab. A 33‐year‐old Asian man developed bilateral lacrimal gland and submandibular salivary gland swelling with cervical lymphadenopathy. Biopsies of the affected tissues revealed reactive follicular hyperplasia. Seven years later, he presented with bilateral retinal hemorrhages due to hyperviscosity syndrome from profound polyclonal increase in IgG, including marked IgG4 elevation. Despite plasmapheresis, overproduction of IgG continued and he was refractory to systemic steroids, azathioprine, interferon alpha, and cyclophosphamide. IgG4‐RD was suspected following a myocardial infarction and detection of aneurysmal coronary arteries indicating large vessel vasculitis. Review of the cervical lymph node and lacrimal gland biopsies with immunohistochemical staining for IgG4‐positive plasma cells confirmed IgG4‐RD. B‐cell depletion with rituximab produced a partial response, but clinical symptoms and elevated protein levels persisted. Fludarabine was added to rituximab to suppress T‐cell activity, and this resulted in an excellent clinical and biochemical response. Combination therapy with fludarabine and rituximab in IgG4‐RD has not previously been reported and can be considered in patients with severe refractory disease.     

Surface proteins of Setaria cervi induce inflammation in macrophage through Toll‐like receptor 4 (TLR4)‐mediated signalling pathway

Lymphatic filariasis is a vectorborne parasitic disease that results in morbidities, disabilities and socio‐economic loss each year globally. Inflammatory consequences associated with any form of filariasis have drawn special attention. However, the molecular insight behind the inflammation of host macrophage (MФ) is considered as one of the shaded areas in filarial research. Herein, major emphasis was given to study the signalling pathway of MФ inflammation induced by surface proteins (SPs) of filarial parasite through in vitro and in vivo approaches. Twenty‐four hours of in vitro stimulation of Raw MФs with endotoxin‐free SPs of Setaria cervi resulted in the secretion of pro‐inflammatory cytokines (TNF‐α and IL‐1β) that revealed induction of inflammation, which was found to be elicited from classical NF‐кB activation. Moreover, this NF‐кB activation was found to be signalled from TLR4 and mediated by the downstream signalling intermediates, viz. MyD88, pTAK1 and NEMO. In vivo studies in adult Wistar rats, experimentally injected with SPs, clearly supported the outcomes of in vitro experiments by showing higher degree of inflammation rather classical activation of the peritoneal MФs. Therefore, SPs from S. cervi cuticle could be responsible for the induction of pro‐inflammatory response in MФ, which appears to be propagated through TLR4‐NF‐кB route.