The nexus between atopic disease and autoimmunity: a review of the epidemiological and mechanistic literature.

There has been considerable interest in defining the relationship between the expression of allergic and autoimmune diseases in populations of patients. Are patients with autoimmune disease 'protected' from developing allergic (immunoglobulin E-mediated) diseases? Does the establishment of an atopic phenotype reduce the risk of the subsequent development of autoimmune diseases? Although there are clinical studies addressing this question, methodological problems, particularly in identification of atopic subjects, limits their usefulness. Moreover, an immune-based explanation of the observed epidemiological findings has relied on a paradigm that is currently undergoing increased scrutiny and modification to include newly defined effector cell subsets and the interaction between genetic and environmental factors, such as early endotoxin or mycobacterial exposure. To address this question, we reviewed a series of clinical reports that addressed coincidence or co-prevalence of atopy with four autoimmune diseases: psoriasis, rheumatoid arthritis, multiple sclerosis and type I diabetes mellitus. We present a model whereby active T helper type 1 (Th1) inflammation may suppress the development of atopy, and atopy may suppress the severity but not necessarily the onset of autoimmunity, and then discuss our model in the context of mechanisms of adaptive immunity with particular reference to the Th1/Th2 paradigms. Because the ultimate goal is to ameliorate or cure these diseases, our discussion may help to predict or interpret unexpected consequences of novel therapeutic agents used to target autoimmune or atopic diseases.

Acetylcholine receptor alpha subunit mRNA expression in human thymus: augmented expression in myasthenia gravis and upregulation by interferon-gamma.

Previous studies by us and others have demonstrated the expression of acetylcholine receptors on epithelial cells in the thymus of myasthenia gravis (MG) and control subjects. In the present experiments, we used a reverse transcription-polymerase chain reaction (RT-PCR) to analyze the profile of the two major isoforms of the alpha chain of these receptors (AChRalpha), P3A- and P3A+, in thymus tissue obtained from MG and control subjects and a human thymic epithelial cell line (TEC9). In addition, using a semiquantitative RT-PCR, we compared the amounts of P3A- and P3A+ mRNA expressed in thymic tissue obtained from these two sources and determined if their expression in TEC9 is modulated by cytokines. We found that mRNAs encoding P3A- and P3A+ are expressed at approximately a 5:1 ratio in both MG and control thymus tissue. This contrasts with skeletal muscle where mRNAs encoding these isoforms are expressed equally. A pattern of preferential P3A- vs P3A+ mRNA expression was also observed in TEC9. We observed 2.8-fold greater expression of both isoforms in MG than in control thymus. Expression of both isoforms in TEC9 was enhanced significantly by treatment with interferon-gamma whereas IL-1alpha, IL-4, and IL-6 had no effect. Thus, there is differential regulation of AChRalpha variants in thymus and TEC relative to muscle and interferon-gamma represents a novel regulator of AChRalpha mRNA expression. MG thymus is distinguished by increased expression of both isoforms of this autoantigen, a finding that may reflect enhancement of transcription by local microenvironmental factors.

In vivo inflammatory response to a prototypic B cell superantigen: elicitation of an Arthus reaction by staphylococcal protein A.

Staphylococcal protein A (SpA) is representative of a new class of Ags, the B cell superantigens (SAgs). These SAgs, unlike conventional Ags, bind to the Fab regions of Ig molecules outside their complementarity-determining regions. In addition, B cell SAgs can react with a substantial amount of a host's serum Igs by virtue of their ability to interact with many members of an entire variable heavy chain (VH) or variable light chain gene family. For example, SpA reacts with the Fabs of most human Igs using heavy chains from the VH3 gene family (VH3+). Members of this gene family are expressed on 30 to 60% of human peripheral B cells. We sought to determine whether the interaction of a B cell SAg with its reactive Igs can elicit immune complex-mediated tissue injury. Using the Arthus reaction in rabbits as an in vivo model of immune complex-mediated tissue inflammation, we demonstrated that untreated rabbits, which were administered SpA intradermally (i.d.), do not develop a cutaneous inflammatory response. However, when rabbits were pretreated i.v. with human IgG (hIgG), i.d. injections of SpA induced an inflammatory response with the classical histologic features of an Arthus reaction. To determine whether this Arthus-like response occurred via a B cell superantigenic mechanism, the rabbits were pretreated with VH3-depleted hIgG and then were administered SpA i.d. We found that the induction of a prominent inflammatory response by SpA was dependent upon the presence of VH3+ molecules in the hIgG pretreatment. These results provide compelling evidence that an interaction of the B cell SAg, SpA, with its reactive (VH3+) IgGs leads to an immune complex-mediated inflammatory response in vivo.

Complement activation by a B cell superantigen.

Staphylococcal protein A (SpA), acting as a B cell superantigen, binds to the Fab region of human VH3+ Igs. Using SpA abrogated of its IgG Fc binding activity (Mod SpA) as a model B cell superantigen, we determined whether such an interaction causes complement activation. Addition of Mod SpA to human serum led to complement consumption and the generation of C3a. To determine whether this complement activation 1) was due to an interaction between VH3+ Igs and the Fab binding site of SpA and 2) proceeded via the classical complement pathway, we tested a panel of monoclonal IgM proteins for the ability to hind C1q following interaction with SpA. C1q binding was restricted to SpA-reactive, VH3+ IgM proteins. To formally determine whether the binding of SpA to the reactive VH3+ IgM proteins led to complement activation, we reconstituted the serum from a hypogammaglobulinemic patient with monoclonal IgM proteins and measured complement consumption and C3a generation following the addition of Mod SpA. We observed complement consumption and C3a production only in Mod SpA-treated serum reconstituted with a VH3+, SpA-binding, IgM protein. Taken together, these results provide compelling evidence that the interaction of the Fab binding site of SpA and VH3+ Igs can lead to complement activation via the classical pathway. This novel interaction may have significant implications for the in vivo properties of a B cell superantigen.

Practice parameters for the diagnosis and management of immunodeficiency. The Clinical and Laboratory Immunology Committee of the American Academy of Allergy, Asthma, and Immunology (CLIC-AAAAI)

In this brief review, only the most useful immunologic tests available for defining host defects that lead to susceptibility to infection have been emphasized. It should be pointed out that those evaluations and tests ordered by the physician will rule out the vast majority of the currently recognized defects. Finally, it is important that any patients identified as abnormal by these screening tests be characterized as fully as possible in centers specializing in these diseases before therapy is initiated, since what may appear to be a simple diagnosis on the surface may be an indicator of more complex underlying problems.

B-cell superantigens: definition and potential impact on the immune response.

Superantigens have been extremely helpful tools in exploring fundamental questions in immunobiology including mechanisms of cell activation, tolerance, and autoimmunity. Until recently, attention has been focused exclusive on T-cell superantigens. However, new data suggest that there are superantigens that directly activate B cells. By definition, these agents (1) stimulate a high frequency of B cells, (2) target B cells that have restricted usage of VH or VL family genes, and (3) bind to immunoglobulins outside the sites that bind conventional antigens. A candidate B-cell superantigen that has received considerable attention in this laboratory is staphylococcal protein A. This agent is best known to the immunologist because of its ability to bind to the Fc fragment of IgG. This binding has been localized to two alpha-helical structures on each of four or five homologous regions that comprise the extracellular domain of protein A. However, it is now clear that protein A contains a second site that binds to determinants on the Fab regions of certain immunoglobulins independently of their heavy-chain isotype. In man this so-called alternative site appears to bind only to immunoglobulins that utilize heavy-chain genes of the VH3 subfamily. In the mouse this type of binding is restricted to immunoglobulins using heavy chains belonging to the S107 and J606 VH families. In this review, we examine the growing list of microbial products that dominate B-cell superantigenic properties. Using staphylococcal protein A as a model for a B-cell superantigen, we consider the potential impact of this novel class of antigens on the immune response. We focus on the ability of B-cell superantigens to influence the expression of the B-cell repertoire. In addition, we consider the hypothesis that the interaction of a B-cell superantigen with its reactive serum immunoglobulins activates the classical complement cascade and thus represents a powerful stimulant of tissue inflammation.

Staphylococcus aureus Cowan I-induced human immunoglobulin responses: preferential IgM rheumatoid factor production and VH3 mRNA expression by protein A-binding B cells.

Protein A (PA), a cell wall component of SAC, activates human B cells by cross-linking the Fabs of membrane immunoglobulins. Recent data indicate that PA binds only to Fabs that use VH3 heavy chains, and thus it has been designated as a B-cell superantigen. We previously reported that Staphylococcus aureus Cowan I (SAC)-induced IgM rheumatoid factor (RF) by human PBMC was mediated by PA. Therefore, we sought to determine if SAC-induced IgMRF production was confined to PA-binding B cells and if these B cells were enriched for the expression of VH3 heavy chains. We observed that the elicitation of IgMRF in response to SAC was limited to a subset of B cells that bind PA and that this subset was enriched for VH3 mRNA expression. Taken together, these results suggest that IgMRFs produced in response to SAC are enriched for usage of VH3 heavy chains. Thus, this SAC-induced autoantibody response appears to represent a new B-cell superantigenic property of PA.

Serum tryptase in idiopathic anaphylaxis: a case report and review of the literature.

Anaphylaxis is a life-threatening disease that characteristically presents with multiple arrays of dermatologic, respiratory, cardiovascular, and gastrointestinal derangements, in general, suddenly after exposure to an allergen. It can, however, occur without an identifiable precipitant or event, and this well-defined entity has been called idiopathic anaphylaxis. The diagnosis of idiopathic anaphylaxis is made after an appropriate allergic evaluation and exclusion of a provocative trigger. We report an unusual case of manifesting with gastroenteritis, urticaria, hypotension, and syncope. Measurement of serum tryptase, a mast cell enzyme, was used to substantiate the diagnosis. Tryptase level is a useful test that can be used to help diagnose this potentially fatal disease.

The high affinity Fc gamma receptor (CD64) induces phagocytosis in the absence of its cytoplasmic domain: the gamma subunit of Fc gamma RIIIA imparts phagocytic function to Fc gamma RI.

The high affinity Fc gamma receptor, Fc gamma RI, is unique among the three classes of macrophage Fc gamma receptors not only in its affinity for IgG, but also in the structure of its cytoplasmic domain. Fc gamma RIIA and the gamma subunit of Fc gamma RIIIA have tyrosine-containing motifs within their cytoplasmic domains that are phosphorylated when crosslinked and that are required for phagocytosis by COS-1 cell transfectants. In contrast to these other Fc gamma receptors, Fc gamma RI does not contain cytoplasmic tyrosines and does not induce phagocytosis in COS-1 transfectants. We transfected wild-type (WT) and mutant (MT) Fc gamma RI lacking the cytoplasmic domain into COS-1 cells and murine macrophages and assessed phagocytosis using IgG-coated red blood cells (RBCs) and RBCs conjugated with Fab anti-human Fc gamma RI monoclonal antibody (mAb). Fc gamma RI, in contrast to Fc gamma RIIA, did not induce phagocytosis in COS cells. However, both WT and MT Fc gamma RI induced phagocytosis in murine macrophages, and phagocytosis was inhibited by the tyrosine kinase inhibitor tyrphostin 23. Human monocytes also phagocytosed Fc gamma RI-targeted RBCs, and activation of Fc gamma RI on monocytes with Fab anti-Fc gamma RI induced phosphorylation of Fc gamma RII on tyrosine residues. However, Fc gamma RI activation of Fc gamma RI-Fc gamma RIIA COS-1 cotransfectants did not induce tyrosine phosphorylation of Fc gamma RIIA, and coexpression of Fc gamma RI and Fc gamma RIIA in COS cells did not confer Fc gamma RI phagocytic capability. In contrast, coexpression in COS-1 cells of Fc gamma RI with the gamma subunit of Fc gamma RIIIA conferred phagocytic function to both Fc gamma RI and the MT Fc gamma RI lacking the cytoplasmic domain. Thus, Fc gamma RI does not require its cytoplasmic domain to mediate a phagocytic signal and interacts with the gamma subunit of Fc gamma RIIIA to induce phagocytosis.

Insertion of cytoplasmic tyrosine sequences into the nonphagocytic receptor Fc gamma RIIB establishes phagocytic function.

Receptors for the Fc domain of IgG on cells of hematopoietic lineage perform important functions, including stimulation of the ingestion of IgG-coated cells. In examining the function of Fc gamma receptor isoforms by transfection into COS-1 cells, we have observed that Fc gamma RIIA induces the binding and phagocytosis of IgG-sensitized RBCs (EA) and that transfected COS-1 cells can serve as a model for examining the molecular structures involved in mediating a phagocytic signal. We now report that COS-1 cell transfectants expressing the isoforms Fc gamma RIIB1 and Fc gamma RIIB2 and a Fc gamma RIIA mutant without a cytoplasmic tail efficiently bind EA but do not mediate their phagocytosis. Furthermore, wild-type Fc gamma RIIA, but not Fc gamma RIIB1 or Fc gamma RBII2, was phosphorylated on tyrosine upon receptor activation. Tyrphostin 23, which alters tyrosine kinase activity, inhibited the phagocytosis of EA and reduced the phosphorylation of Fc gamma RIIA on tyrosine. Fc gamma RIIB1 and Fc gamma RIIB2 contain one copy of the cytoplasmic sequence YXXL/I implicated in signal transduction, whereas Fc gamma RIIA contains two copies. We therefore inserted YXXL/I sequences at different sites in Fc gamma RIIB2. Low levels of phagocytosis were observed in a Fc gamma RIIB2 mutant bearing the Fc gamma RIIA sequence YMTL and higher levels of phagocytosis were observed in a second Fc gamma RIIB2 mutant that contained both the upstream YMTL and an additional downstream tyrosine-containing motif. Activation of this mutant receptor also induced receptor tyrosine phosphorylation. Thus, these studies indicate that both the number and placement of YXXL sequences in the cytoplasmic domain of the Fc gamma RII receptor family affect both receptor tyrosine phosphorylation and phagocytic competence.

Polyautoimmune syndrome in common variable immunodeficiency.

Common variable immunodeficiency (CVI) is a heterogenous disorder with hypogammaglobulinaemia and multiple bacterial infections primarily involving the sinopulmonary tract. CVI patients have been known to have an increased tendency to develop autoimmune manifestations. Commonly associated autoimmune diseases include immune thrombocytopenic purpura, autoimmune haemolytic anaemia, and rheumatoid arthritis. In this paper we report a case of CVI presenting with multiple unusual autoimmune diseases including parotitis, vitiligo, atrophic gastritis, pernicious anaemia, and primary biliary cirrhosis. To our knowledge, this is the first case of CVI with polyautoimmunity and antimitochondria antibody. Recognition of this association is important because early diagnosis and treatment can greatly influence the prognosis.

Hypogammaglobulinemia and rheumatic disease.

Primary hypogammaglobulinemia describes a heterogeneous group of immunoglobulin disorders mainly composed of X-linked agammaglobulinemia, common variable immunodeficiency, and selective immunoglobulin (Ig) A deficiency. The most serious problems are related to recurrent infections with high-grade encapsulated bacteria. However, a wide variety of rheumatologic disorders also occur in association with hypogammaglobulinemic states. Septic arthritis with usual bacterial pathogens such as Staphylococcus aureus, and unusual bacteria such as Mycoplasma and Ureaplasma species, have been described in these patients. An aseptic nonerosive polyarticular arthritis that resembles rheumatoid arthritis is seen in 10% to 30% of hypogammaglobulinemic patients. Autoimmune disorders such as immune thrombocytopenic purpura, immune hemolytic anemia, juvenile rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, essential mixed cryoglobulinemia, chronic active hepatitis, and sarcoidosis have been reported in hypogammaglobulinemic patients. Finally, to complicate matters, many disease-modifying antirheumatic drugs, including gold, D-penicillamine, sulfasalazine, azathioprine, and cyclophosphamide, cause symptomatic hypogammaglobulinemia in some patients.

Calcium signalling by the high affinity macrophage Fc gamma receptor requires the cytosolic domain.

Hematopoietic cells express multiple receptors which bind the Fc domain of IgG. We utilized transfection of COS-1 cells, a cell line which lacks endogenous Fc receptors, to study the expression and function of Fc gamma RI, the high affinity Fc gamma receptor in the absence of other Fc gamma receptors. Fc gamma RI was efficiently expressed in transiently transfected COS-1 cells as measured by flow cytometry and the binding of IgG sensitized RBCs (EA). In addition, analysis at the single cell level demonstrated that individually transfected COS-1 cells release cytosolic free Ca2+ [(Ca2+)i] upon activation with anti-Fc gamma RI antibody. The calcium response required Fc gamma RI cross-linking. COS-1 cells transfected with mutant Fc gamma RI lacking the cytosolic domain expressed Fc gamma receptors and bound EA as well as wild type receptors, but failed to induce an increase in [Ca2+]i. These data indicate that Fc gamma RI in the absence of other Fc gamma receptors mediates a calcium signal and that the cytoplasmic domain of Fc gamma RI contains the elements required for calcium dependent signal transduction.