Immunity In Contrast Research Articles

Immunology of COVID-19 and its clinical implications for therapy

The newly emerged novel coronavirus (COVID-19) is highly contagious, large enveloped, single-stranded, nonsegmented, positive-sense RNA viruse that belong to coronaviridae family and genus Beta coronavirus The viruses of coronaviridae family are further divided into two subfamilies;Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus COVID-19 show close similarities to SARS-CoV due to phylogenetic relationship and genome structure Word Health Organisation has designated the current pandemic of SARS-CoV-2 infection as COVID-19 The virus shows high infectivity and mainly transmitted in the form of droplets with an incubation period of about 4-5 days The onset of symptoms in patients is usually within 11-12 days Here, Rao and Gupta discuss the immunology of COVID-19

Designation of Autoinflammatory Skin Manifestations With Specific Genetic Backgrounds.

“Autoinflammatory disease (AiD)” has first been introduced in 1999 when the responsible gene for the familial Hibernean fever or autosomal dominant-type familial Mediterranean fever-like periodic fever syndrome was reportedly identified as tumor necrosis factor receptor superfamily 1. Linked with the rapid research progress in the field of innate immunity, “autoinflammation” has been designated for dysregulated innate immunity in contrast to “autoimmunity” with dysregulated acquired immunity. As hereditary periodic fever syndromes represent the prototype of AiD, monogenic systemic diseases are the main members of AiD. However, skin manifestations provide important clinical information and there are even some AiDs originating from skin diseases. Recently, AiD showing psoriasis and related keratinization diseases have specifically been designated as “autoinflammatory keratinization diseases (AiKD)” and CARD14-associated psoriasis and deficiency of interleukin-36 receptor antagonist previously called as generalized pustular psoriasis are included. Similarly, a number of autoinflammatory skin diseases can be proposed; autoinflamatory urticarial dermatosis (AiUD) such as cryopyrin-associated periodic syndrome; autoinflammatory neutrophilic dermatosis (AiND) such as pyogenic sterile arthritis, pyoderma gangrenosm, and acne syndrome; autoinflammatory granulomatosis (AiG) such as Blau syndrome; autoinflammatory chilblain lupus (AiCL) such as Aicardi-Goutieres syndrome; autoinflammatory lipoatrophy (AiL) such as Nakajo-Nishimura syndrome; autoinflammatory angioedema (AiAE) such as hereditary angioedema; and probable autoinflammatory bullous disease (AiBD) such as granular C3 dermatosis. With these designations, skin manifestations in AiD can easily be recognized and, even more importantly, autoinflammatory pathogenesis of common skin diseases are expected to be more comprehensive.

Novel influenza vaccine M2SR protects against drifted H1N1 and H3N2 influenza virus challenge in ferrets with pre-existing immunity

Current influenza vaccines do not provide effective protection against heterologous influenza viruses. The ability of the novel M2SR influenza vaccine to protect against drifted influenza viruses was evaluated in naïve ferrets and in ferrets with pre-existing immunity to influenza. In naïve ferrets, M2SR provided similar protection against drifted challenge viruses as the comparator vaccine, FluMist®. However, in ferrets with pre-existing immunity, M2SR provided superior protection than FluMist in two model systems.In the first model, ferrets were infected with influenza A H1N1pdm and influenza B viruses to mimic the diverse influenza exposure in humans. The pre-infected ferrets, seropositive to H1N1pdm and influenza B but seronegative to H3N2, were then vaccinated with H3N2 M2SR or monovalent H3N2 FluMist virus (A/Brisbane/10/2007, clade 1) and challenged 6 weeks later with a drifted H3N2 virus (clade 3C.2a). Antibody titers to Brisbane/10/2007 were higher in M2SR vaccinated ferrets than in FluMist vaccinated ferrets in the pre-infected ferrets whereas the opposite was observed in naïve ferrets. After challenge with drifted H3N2 virus, M2SR provided superior protection than FluMist monovalent vaccine.In the second model, the impact of homologous pre-existing immunity upon vaccine-induced protection was evaluated. Ferrets, pre-infected with H1N1pdm virus, were vaccinated 90 days later with H1N1pdm M2SR or FluMist monovalent vaccine and challenged 6 weeks later with a pre-pandemic seasonal H1N1 virus, A/Brisbane/59/2007 (Bris59). While cross-reactive serum IgG antibodies against the Bris59 HA were detected after vaccination, anti-Bris59 hemagglutination inhibition antibodies were only detected post-challenge. M2SR provided better protection against Bris59 challenge than FluMist suggesting that homologous pre-existing immunity affected FluMist virus to a greater degree than M2SR.These results suggest that the single replication intranasal M2SR vaccine provides effective protection against drifted influenza A viruses not only in naïve ferrets but also in those with pre-existing immunity in contrast to FluMist viruses.

Dynamic Changes in the Splenic Transcriptome of Chickens during the Early Infection and Progress of Marek\u2019s Disease

Gallid alphaherpesvirus 2 (GaHV2) is an oncogenic avian herpesvirus inducing Marek’s disease (MD) and rapid-onset T-cell lymphomas. To reveal molecular events in MD pathogenesis and tumorigenesis, the dynamic splenic transcriptome of GaHV2-infected chickens during early infection and pathogenic phases has been determined utilizing RNA-seq. Based on the significant differentially expressed genes (DEGs), analysis of gene ontology, KEGG pathway and protein-protein interaction network has demonstrated that the molecular events happening during GaHV2 infection are highly relevant to the disease course. In the ‘Cornell Model’ description of MD, innate immune responses and inflammatory responses were established at early cytolytic phase but persisted until lymphoma formation. Humoral immunity in contrast began to play a role firstly in the intestinal system and started at late cytolytic phase. Neurological damage caused by GaHV2 is first seen in early cytolytic phase and is then sustained throughout the following phases over a long time period. During the proliferative phase many pathways associated with transcription and/or translation were significantly enriched, reflecting the cell transformation and lymphoma formation. Our work provides an overall view of host responses to GaHV2 infection and offers a meaningful basis for further studies of MD biology.

Development, phenotype, and function of non-conventional B cells.

Three populations of B cells develop in fetal life: B1, B2 and marginal zone B cells. B1 cells play important roles in innate immunity in contrast to B2 cells that perform the conventional roles in adaptive immunity. B1 cells were first identified in mice based on their expression of CD5 and spontaneous secretion of IgM. B1 cells were subsequently found to have unique developmental, phenotype, tissue distribution, and functional characteristics that differ from B2 cells. These phenotypic and functional differences allow B1 cells to play important roles in immunity and homeostasis, but be implicated in autoimmune disease. The presence of B1 cells has been examined in other species including humans, primates, rabbits, guinea pigs, cattle, pigs, and horses. Here we review the known developmental and functional differences between B1 and B2 cells, and discuss the evidence of the presence of homologous population of cells in different species.

Abstract 512: Leukemia-specific immunity in healthy individuals and patients post-transplant targets phosphorylated tumor antigens

Abstract The major antigenic targets of endogenous tumor immunity remain unknown although many minor targets have been identified. At a proteomic level, cancer is considered a disease of deregulated cell signal pathway activation; therefore we investigated whether endogenous anti-tumor immunity targeted phosphorylated protein antigens generated through the transformation process. In previous work we identified phosphorylated peptides differentially expressed on primary leukemia samples: 58 for acute myeloid leukemia (AML) samples and 31 for chronic lymphocytic leukemia (CLL). Many of the identified phosphopeptides were derived from established leukemogenic oncoproteins such as MLL, RUNX1, c-Myc, EP300, CXCR4, SKI, GRK, CD19, CD20, NCOA1, and TLK1 among others and differentially expressed between malignant and healthy counterpart tissue (splenic B cells, bone marrow). Using ELISpot and HLA-phosphopeptide multimers, we screened 10 healthy donors, 17 patients in complete remission with underlying AML and 14 patients with CLL. Healthy donors (HD) exhibited a highly heterogeneous reactivity against this panel of phosphoantigens but all responded to at least 10/57 phosphoantigens tested. Further investigation revealed this immunity resided within the central memory CD8 T cell compartment at the same magnitude of responses as those against influenza and adenovirus. By contrast only 2/12 AML and 5/14 CLL patients demonstrated anti-phosphopeptide immunity compared to 10/10 HDs (≥2< 0.01 for both). In contrast immunity against viral and mitogenic stimuli was similar between patients and HDs. Following allogeneic stem cell transplantation the majority (10/12) AML patients reconstituted anti-phosphopeptide immunity. In some cases dramatic expansions, of similar magnitude to cytomegalovirus responses, were observed approaching 1% of CD8 T cells for a single phosphopeptide epitope. In CLL, none of whom were transplanted, we found that over the study period of 12 months that among the patients with anti-phosphopeptide immunity only 1 of 5 patients required treatment compared to 4 of 9 patients requiring treatment where no anti phosphopeptide responses were seen (≥2=NS). Importantly, ex vivo expanded phosphopeptide specific T cells isolated from both healthy individuals and patients post-transplant were able to kill both HLA-matched primary leukemia samples and AML cell lines in a phosphopeptide-specific manner. These data suggest a prominent role for tumor-associated phosphopeptide antigens in the prevention and control of haematolymphoid disease in man. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 512. doi:1538-7445.AM2012-512

Mucosal Immune System and M Cell-targeting Strategies for Oral Mucosal Vaccination

Vaccination is one of the most effective methods available to prevent infectious diseases. Mucosa, which are exposed to heavy loads of commensal and pathogenic microorganisms, are one of the first areas where infections are established, and therefore have frontline status in immunity, making mucosa ideal sites for vaccine application. Moreover, vaccination through the mucosal immune system could induce effective systemic immune responses together with mucosal immunity in contrast to parenteral vaccination, which is a poor inducer of effective immunity at mucosal surfaces. Among mucosal vaccines, oral mucosal vaccines have the advantages of ease and low cost of vaccine administration. The oral mucosal immune system, however, is generally recognized as poorly immunogenic due to the frequent induction of tolerance against orally-introduced antigens. Consequently, a prerequisite for successful mucosal vaccination is that the orally introduced antigen should be transported across the mucosal surface into the mucosa-associated lymphoid tissue (MALT). In particular, M cells are responsible for antigen uptake into MALT, and the rapid and effective transcytotic activity of M cells makes them an attractive target for mucosal vaccine delivery, although simple transport of the antigen into M cells does not guarantee the induction of specific immune responses. Consequently, development of mucosal vaccine adjuvants based on an understanding of the biology of M cells has attracted much research interest. Here, we review the characteristics of the oral mucosal immune system and delineate strategies to design effective oral mucosal vaccines with an emphasis on mucosal vaccine adjuvants.

Late-onset cytomegalovirus disease in patients with solid organ transplant

To review existing data regarding late cytomegalovirus disease occurring after antiviral prophylaxis. There is a continued debate as to the respective merits of the preemptive and the prophylactic approach to prevent cytomegalovirus disease after transplantation. Arguably, by allowing some infection, the preemptive approach helps build immunity in contrast to prophylaxis, explaining the occurrence of late cytomegalovirus disease in the latter approach. No study comparing directly both approaches is large enough to definitely determine whether the preemptive approach leads to a faster development of immune response protective from late disease nor whether late disease is clinically different after prophylaxis compared to early cytomegalovirus diseases. While risk factors for late cytomegalovirus disease all point to a delay in mounting immune responses, there are no identified markers that would help predict the risk for late disease at the time of prophylaxis discontinuation. Various approaches to prevent late cytomegalovirus disease have been developed: prolonged prophylaxis, microbiological surveillance and preemptive treatment after prophylaxis discontinuation. Considering the identifying risk factors for late disease, it would also make sense to envision vaccinating cytomegalovirus-seronegative recipients. The best approach to prevent or manage late cytomegalovirus disease associated with cytomegalovirus prophylaxis remains to be defined.

IFN-gamma-mediated prevention of graft-versus-host disease: pharmacodynamic studies and influence on proliferative capacity of chimeric spleen cells.

Recently we demonstrated that prolonged administration of IFN-gamma prevented the development of GVHD in a MHC-mismatched murine BMT model. Treatment with IFN-gamma allowed the development of mature donor-derived allo-tolerant immunocompetent cells in complete chimeric recipients. Here we present data on the pharmacodynamics of this cytokine-mediated protection against GVHD. Treatment with 50000 U IFN-gamma twice weekly for a period of 5 weeks, starting at the day of BMT, was shown to be the optimal treatment protocol, resulting in complete prevention of GVHD-related mortality. Treatment during 1 week with a three-fold higher weekly dose of IFN-gamma (50000 U six times) did not result in significantly improved survival. The start of IFN-gamma administration was a critical factor since a delay of 3 days from the time of BMT resulted in substantial GVHD-induced mortality. Furthermore, it was shown that IFN-gamma treatment inhibited the spontaneous and Con-A-induced proliferation of T cells at 7-14 days after BMT, which is the critical period for the initiation of acute GVHD. However, long-term survivors after IFN-gamma treatment showed a recovery of immunity in contrast to long-term survivors of saline-injected animals, as tested by Con-A responsiveness. It seems that injection of high dose IFN-gamma suppresses the response of potentially alloreactive donor T cells during what normally is the initiation phase of the GVH reaction (GVHR), resulting in the abrogation of GVHD.

Mucosal immunity: an overview and studies of enteric and respiratory coronavirus infections in a swine model of enteric disease

Based on the tenet of a common mucosal immune system, antigenic stimulation at one mucosal site results in the distribution of antigen-specific IgA precursor cells to distant mucosal sites. However, recent studies suggest that functional compartmentalization and limited reciprocity may exist within some components of the common mucosal immune system. Although oral immunization is often very effective in inducing immunity to respiratory pathogens, the converse (respiratory immunization to prevent enteric diseases) may not be as effective. To address this question and to study interactions between the bronchus-associated (BALT) and gut-associated (GALT) lymphoid tissues related to protective immunity, we used as a model two antigenically related porcine coronaviruses which replicate primarily in the intestine (transmissible gastroenteritis virus, TGEV) or respiratory tract (porcine respiratory coronavirus, PRCV). The tissue distribution and magnitude of the antibody secreting cell (ASC) responses (measured by ELISPOT) and cell-mediated immune responses (measured by lymphoproliferative assays, LPA) coincided with the viral tissue tropisms. Immunization via GALT (gut infection with TGEV) elicited high numbers of IgA ASC and high LPA responses in GALT (gut lamina propria, LP or mesenteric lymph nodes, MLN), but lower responses in BALT (bronchial lymph nodes, BLN) and induced complete protection against enteric TGEV challenge. In contrast immunization via BALT (respiratory infection with PRCV) elicited systemic type responses (high numbers of IgG ASC in the BLN), but few ASC and low LPA responses in the gut LP or MLN and induced only partial protection against enteric TGEV challenge. Thus administration of vaccines intranasally may not be optimally effective for inducing intestinal immunity in contrast to the reported efficacy of oral vaccines for inducing respiratory immunity.

Correlation of tumor specific delayed type hypersensitivity reaction and tumor protection to SV40-induced mKSA fibrosarcoma.

Mice immunized by excision of a primary, subcutaneously growing SV40-induced mKSA solid tumor which resisted challenge of homologous tumor cells administered at a contralateral site, were found to develop a specific DTH response to SV40 tumor associated transplantation antigens (TATA). In a two-way criss-cross experiment, this DTH response (assessed by direct challenge) was found to be one-way SV40 specific in that chemically induced, non SV40, MCA tumor failed to elicit a DTH response in mice primed by excision of mKSA tumor. These mice also showed a corresponding one-way specific protection against challenge with live homologous mKSA sarcoma cells. In contrast immunization and challenge of MCA-excised mice with either MCA or mKSA tumor cells, exhibited cross-reactivity in both DTH response and protection against either tumor. Unlike this cross-immunity by the direct challenge method, transfer of "immune" spleen cells from mKSA or MCA excision-primed mice demonstrated a specific DTH response and protection to the original immunizing, homologous but not heterologous tumor. Tumor resistant, DTH-primed mice remained DTH reactive to the primary tumor cells over a period of 4 weeks. Characterization of the splenic T-DTH cells in mice primed by excision of mKSA tumor, indicated a Lyt 1+2+ phenotype of cells conferring both the DTH response and the immune protection against mKSA sarcoma in a local (Winn) adoptive transfer assay, thus reinforcing the correlation between the DTH response and the antitumor protection.

Immunization of susceptible BALB/c mice against Leishmania braziliensis, : I. Resistance induced using as immunogen adherent or nonadherent cells from infected mice

Strategies to produce resistance to infection with Leishmania braziliensis in BALB/c mice are described. Mice infected with virulent parasites were used as spleen cell donors (adherent/ nonadherent cells) with which to immunize naive recipients which were themselves later challenged with the organism. Immunization with both adherent and nonadherent spleen cells (but not serum) in the presence of adjuvant led to protection. In the former case it seems that an immunogenic form of parasite antigen presented in the context of MAC-1 + adherent cells was responsible. In contrast immunization with nonadherent spleen cells depended upon the presence of Thy-1.2 + Lyt-1 + cells in the spleen cell preparation from infected animals. Immunization with adherent cells, but not with nonadherent cells, led to the development of a population of Thy-1.2 + spleen cells capable of adoptively transferring resistance to naive mice.