Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency.

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4 T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs).

Vaccine-induced ErbB (EGFR/HER2)-specific immunity in spontaneous canine cancer.

Epidermal Growth Factor Receptor (EGFR) is overexpressed on a number of human cancers, and often is indicative of a poor outcome. Treatment of EGFR/HER2 overexpressing cancers includes monoclonal antibody therapy (cetuximab/trastuzumab) either alone or in conjunction with other standard cancer therapies. While monoclonal antibody therapy has been proven to be efficacious in the treatment of EGFR/HER2 overexpressing tumors, drawbacks include the lack of long-lasting immunity and acquired resistance to monoclonal therapy.

Seroprevalence of Borrelia burgdorferi, B. miyamotoi, and Powassan Virus in Residents Bitten by Ixodes Ticks, Maine, USA.

We conducted a serosurvey of 230 persons in Maine, USA, who had been bitten by Ixodes scapularis or I. cookei ticks. We documented seropositivity for Borrelia burgdorferi (13.

Epidermal growth factor receptor peptide vaccination induces cross-reactive immunity to human EGFR, HER2, and HER3.

Current treatments for tumors expressing epidermal growth factor receptor (EGFR) include anti-EGFR monoclonal antibodies, often used in conjunction with the standard chemotherapy, radiation therapy, or other EGFR inhibitors. While monoclonal antibody treatment is efficacious in many patients, drawbacks include its high cost of treatment and side effects associated with multiple drug infusions. As an alternative to monoclonal antibody treatments, we have focused on peptide-based vaccination to trigger natural anti-tumor antibodies.

Oxidative Modifications in Tissue Pathology and Autoimmune Disease.

Significance: Various autoimmune syndromes are characterized by abnormalities found at the level of tissues and cells, as well as by microenvironmental influences, such as reactive oxygen species (ROS), that alter intracellular metabolism and protein expression. Moreover, the convergence of genetic, epigenetic, and even environmental influences can result in B and T lymphocyte autoimmunity and tissue pathology. Recent Advances: This review describes how oxidative stress to cells and tissues may alter post-translational protein modifications, both directly and indirectly, as well as potentially lead to aberrant gene expression.

Autoantigens: novel forms and presentation to the immune system.

It is clear that lupus autoimmunity is marked by a variety of abnormalities, including those found at a macroscopic scale, cells and tissues, as well as more microenvironmental influences, originating at the individual cell surface through to the nucleus. The convergence of genetic, epigenetic, and perhaps environmental influences all lead to the overt clinical expression of disease, reflected by the presences of autoantibodies and tissue pathology. This review will address several specific areas that fall among the non-genetic factors that contribute to lupus autoimmunity and related syndromes.

Autoimmunity to isomerized histone H2B in systemic lupus erythematosus.

Histone H2B is a common target of autoantibodies in both spontaneous and drug-induced systemic lupus erythematosus (SLE). Recent studies demonstrate that Asp(25) of histone H2B (H2B) spontaneously converts to an isoaspartic acid (isoAsp) in vivo. Our laboratory has demonstrated that the posttranslational modification of an aspartic acid to an isoaspartic acid within self-peptides renders otherwise ignored peptides immunogenic.

Autoantigenesis: the evolution of protein modifications in autoimmune disease.

Protein targets in autoimmune disease vary in location, originating within cells as in system lupus erythematosus (SLE), or found on cell surfaces or in extracellular spaces. The term 'autoantigenesis' is first defined here as the changes that arise in self-proteins as they break self-tolerance and trigger autoimmune B and/or T cell responses. As illustrated in many studies, between 50 and 90% of the proteins in the human body acquire post-translational modification.

Altered immunogenicity of isoaspartate containing proteins.

The development of immune tolerance is dependent on the expression of self-peptides in the thymus and bone marrow during lymphocyte development. However, not all self-antigens are expressed in the thymus, particularly for proteins that become post-translationally modified during other biological processes in a cell. We have found that one such post-translational modification, the spontaneous conversion of an aspartic acid to isoaspartic acid (isoAsp), causes ignored self-antigens to become immunogenic.

Intracellular protein modification associated with altered T cell functions in autoimmunity.

Posttranslational protein modifications influence a number of immunologic responses ranging from intracellular signaling to protein processing and presentation. One such modification, termed isoaspartyl (isoAsp), is the spontaneous nonenzymatic modification of aspartic acid residues occurring at physiologic pH and temperature. In this study, we have examined the intracellular levels of isoAsp residues in self-proteins from MRL(+/+), MRL/lpr, and NZB/W F(1) mouse strains compared with nonautoimmune B10.

Protein repair in the brain, proteomic analysis of endogenous substrates for protein L-isoaspartyl methyltransferase in mouse brain.

Protein L-isoaspartyl methyltransferase (PIMT) catalyzes repair of L-isoaspartyl peptide bonds, a major source of protein damage under physiological conditions. PIMT knock-out (KO) mice exhibit brain enlargement and fatal epileptic seizures. All organs accumulate isoaspartyl proteins, but only the brain manifests an overt pathology.

Isoaspartyl post-translational modification triggers anti-tumor T and B lymphocyte immunity.

A hallmark of the immune system is the ability to ignore self-antigens. In attempts to bypass normal immune tolerance, a post-translational protein modification was introduced into self-antigens to break T and B cell tolerance. We demonstrate that immune tolerance is bypassed by immunization with a post-translationally modified melanoma antigen.

Synapsin I is a major endogenous substrate for protein L-isoaspartyl methyltransferase in mammalian brain.

The accumulation of potentially deleterious L-isoaspartyl linkages in proteins is prevented by the action of protein L-isoaspartyl O-methyltransferase, a widely distributed enzyme that is particularly active in mammalian brain. Methyltransferase-deficient (knock-out) mice exhibit greatly increased levels of isoaspartate and typically succumb to fatal epileptic seizures at 4-10 weeks of age. The link between isoaspartate accumulation and the neurological abnormalities of these mice is poorly understood.

Posttranslational modifications of self-antigens.

Although the immune system has developed mechanisms to distinguish "self" from "non-self," the presence of autoimmune diseases demonstrates that these mechanisms can be bypassed. The posttranslational modification of self-antigens is one way in which "new" antigens are created for which immune tolerance does not exist. We review some of the posttranslationally modified self-antigens associated with autoimmune diseases, how they arise, and how they break immune tolerance.

Protein L-isoaspartyl methyltransferase catalyzes in vivo racemization of Aspartate-25 in mammalian histone H2B.

Protein L-isoaspartyl methyltransferase (PIMT) has been implicated in the repair or metabolism of proteins containing atypical L-isoaspartyl peptide bonds. The repair hypothesis is supported by previous studies demonstrating in vitro repair of isoaspartyl peptides via formation of a succinimide intermediate. Utilization of this mechanism in vivo predicts that PIMT modification sites should exhibit significant racemization as a side reaction to the main repair pathway.

Cytokine and chemokine expression in the central nervous system associated with protective cell-mediated immunity against Cryptococcus neoformans.

Cryptococcus neoformans is a yeast that causes cryptococcosis, a life-threatening disease that develops following inhalation and dissemination of the organisms. C. neoformans has a predilection for the central nervous system (CNS) and mortality is most frequently associated with meningoencephalitis.

A failure to repair self-proteins leads to T cell hyperproliferation and autoantibody production.

It is clear that many factors can perturb T cell homeostasis that is critical in the maintenance of immune tolerance. Defects in the molecules that regulate homeostasis can lead to autoimmune pathology. This simple immunologic concept is complicated by the fact that many self-proteins undergo spontaneous posttranslational modifications that affect their biological functions.

Memory CD4+ T cells do not induce graft-versus-host disease.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Donor T cells that accompany stem cell grafts cause GVHD by attacking recipient tissues; therefore, all patients receive GVHD prophylaxis by depletion of T cells from the allograft or through immunosuppressant drugs. In addition to providing a graft-versus-leukemia effect, donor T cells are critical for reconstituting T cell-mediated immunity.

Posttranslational protein modifications: new flavors in the menu of autoantigens.

Perhaps one of the most elusive areas of study in autoimmunity has been identifying the self-antigens that initially trigger the development of autoimmune responses. Recent work in this area has demonstrated that a number of biochemical modifications that arise in proteins after their translation induce autoimmune responses to otherwise ignored self-proteins. This article will describe those autoimmune diseases in which posttranslational modifications may play a role in initiation of disease, as well as identify how these modifications arise and contribute to the breakdown of immune tolerance.