Allergic myocardial ischemia secondary to ibuprofen, Kounis syndrome. Case report / Isquemia miocárdica alérgica secundaria a ibuprofeno, síndrome de Kounis. Reporte de un caso

Abstract: Background: Kounis syndrome was described in 1991 as the simultaneous occurrence of acute coronary events and anaphylactic allergic reactions. Reports of clinical cases and series of small cases of angina triggered by allergic reactions have been reported for many years. It encompasses concepts such as allergic angina and allergic infarction. Case report: We report a case of a 47-year-old man with a history of fixed drug eruption for 10 years. The patient attended to the hospital with a moderate-intensity chest pain, electrocardiogram was performed which was compatible with acute coronary syndrome without ST-segment elevation; it progressed favorably with treatment by protocol. The subsequent study showed hypersensitivity to non-steroidal anti-inflammatory drugs and cardiovascular tests was negative, and it was concluded as a case of allergic angina. Conclusions: Kounis syndrome is a difficult to diagnose entity that requires a high index of suspicion in the evaluation of patients with chest pain in the Emergency Department.(AU)

Resumen: Antecedentes: El síndrome de Kounis fue descrito en 1991 como la aparición simultánea de eventos coronarios agudos y reacciones alérgicas anafilácticas. Casos clínicos y pequeñas series de casos de angina generada por reacciones alérgicas han sido reportados en varios años. Engloba conceptos como el de angina alérgica e infarto alérgico. Caso clínico: Presentamos un caso clínico de un hombre de 47 años de edad, con antecedentes de eritema fijo medicamentoso desde hace 10 años. Acude al Departamento de Emergencia por presentar dolor torácico de moderada intensidad, se realiza electrocardiograma el cual es compatible con síndrome coronario agudo sin elevación del segmento ST. Evolucionó favorablemente con tratamiento según protocolo. El estudio posterior demostró hipersensibilidad a antiinflamatorios no esteroideos y las pruebas de estratificación de isquemia cardiovascular fueron negativas, por lo que se concluyó como un caso de angina alérgica. Conclusiones: El síndrome de Kounis es una entidad de difícil diagnóstico que requiere un alto índice de sospecha en la valoración de pacientes con dolor torácico en el Departamento de Emergencia.(AU)

Dual-reactive B cells are autoreactive and highly enriched in the plasmablast and memory B cell subsets of autoimmune mice.

Rare dual-reactive B cells expressing two types of Ig light or heavy chains have been shown to participate in immune responses and differentiate into IgG(+) cells in healthy mice. These cells are generated more often in autoreactive mice, leading us to hypothesize they might be relevant in autoimmunity. Using mice bearing Igk allotypic markers and a wild-type Ig repertoire, we demonstrate that the generation of dual-κ B cells increases with age and disease progression in autoimmune-prone MRL and MRL/lpr mice. These dual-reactive cells express markers of activation and are more frequently autoreactive than single-reactive B cells. Moreover, dual-κ B cells represent up to half of plasmablasts and memory B cells in autoimmune mice, whereas they remain infrequent in healthy mice. Differentiation of dual-κ B cells into plasmablasts is driven by MRL genes, whereas the maintenance of IgG(+) cells is partly dependent on Fas inactivation. Furthermore, dual-κ B cells that differentiate into plasmablasts retain the capacity to secrete autoantibodies. Overall, our study indicates that dual-reactive B cells significantly contribute to the plasmablast and memory B cell populations of autoimmune-prone mice suggesting a role in autoimmunity.

Novel method for quantitative ANA measurement using near-infrared imaging.

Antinuclear antibodies (ANA) have been detected in patients with systemic rheumatic diseases and are used in the screening and/or diagnosis of autoimmunity in patients as well as mouse models of systemic autoimmunity. Indirect immunofluorescence (IIF) on HEp-2 cells is the gold standard for ANA screening. However, its usefulness is limited in diagnosis, prognosis and monitoring of disease activity due to the lack of standardization in performing the technique, subjectivity in interpreting the results and the fact that it is only semi-quantitative. Various immunological techniques have been developed in an attempt to improve upon the method to quantify ANA, including enzyme-linked immunosorbent assays (ELISAs), line immunoassays (LIAs), multiplexed bead immunoassays and IIF on substrates other than HEp-2 cells. Yet IIF on HEp-2 cells remains the most common screening method for ANA. In this study, we describe a simple quantitative method to detect ANA which combines IIF on HEp-2 coated slides with analysis using a near-infrared imaging (NII) system. Using NII to determine ANA titer, 86.5% (32 of 37) of the titers for human patient samples were within 2 dilutions of those determined by IIF, which is the acceptable range for proficiency testing. Combining an initial screening for nuclear staining using microscopy with titration by NII resulted in 97.3% (36 of 37) of the titers detected to be within two dilutions of those determined by IIF. The NII method for quantitative ANA measurements using serum from both patients and mice with autoimmunity provides a fast, relatively simple, objective, sensitive and reproducible assay, which could easily be standardized for comparison between laboratories.

Ig allotypic inclusion does not prevent B cell development or response.

B cells expressing two different Ig kappa L chains (allotype included) have been occasionally observed. To determine frequency and function of these cells, we have analyzed gene-targeted mice that carry a human and a mouse Igk C region genes. Using different methodologies, we found that cells expressing two distinct kappa-chains were 1.4-3% of all B cells and that they were present in the follicular, marginal zone, and B1 mature B cell subsets. When stimulated in vitro with anti-IgM, dual kappa surface-positive cells underwent activation that manifested with cell proliferation and/or up-regulation of activation markers and similar to single kappa-expressing B cells. Yet, when activated by divalent reagents that bound only one of the two kappa-chains, dual kappa B cells responded suboptimally in vitro, most likely because of reduced Ag receptor cross-linking. Nonetheless, dual kappa B cells participated in a SRBC-specific immune response in vivo. Finally, we found that Ig allotype-included B cells that coexpress autoreactive and nonautoreactive Ag receptors were also capable of in vitro responses following BCR aggregation. In summary, our studies demonstrate that Ig kappa allotype-included B cells are present in the mouse mature B cell population and are responsive to BCR stimulation both in vitro and in vivo. Moreover, because in vitro activation in response to anti-IgM was also observed in cells coexpressing autoreactive and nonautoreactive Abs, our studies suggest a potential role of allotype-included B cells in both physiological and pathological immune responses.

Receptor editing can lead to allelic inclusion and development of B cells that retain antibodies reacting with high avidity autoantigens.

Receptor editing is a major B cell tolerance mechanism that operates by secondary Ig gene rearrangements to change the specificity of autoreactive developing B cells. In the 3-83Igi mouse model, receptor editing operates in every autoreactive anti-H-2K(b) B cell, providing a novel receptor without additional cell loss. Despite the efficiency of receptor editing in generating nonautoreactive Ag receptors, we show in this study that this process does not inactivate the autoantibody-encoding gene(s) in every autoreactive B cell. In fact, receptor editing can generate allelically and isotypically included B cells that simultaneously express the original autoreactive and a novel nonautoreactive Ag receptors. Such dual Ab-expressing B cells differentiate into transitional and mature B cells retaining the expression of the autoantibody despite the high avidity interaction between the autoantibody and the self-Ag in this system. Moreover, we find that these high avidity autoreactive B cells retain the autoreactive Ag receptor within the cell as a consequence of autoantigen engagement and through a Src family kinase-dependent process. Finally, anti-H-2K(b) IgM autoantibodies are found in the sera of older 3-83Igi mice, indicating that dual Ab-expressing autoreactive B cells are potentially functional and capable of differentiating into IgM autoantibody-secreting plasma cells under certain circumstances. These results demonstrate that autoreactive B cells reacting with ubiquitous membrane bound autoantigens can bypass mechanisms of central tolerance by coexpressing nonautoreactive Abs. These dual Ab-expressing autoreactive B cells conceal their autoantibodies within the cell manifesting a superficially tolerant phenotype that can be partially overcome to secrete IgM autoantibodies.

Transition of arrestin into the active receptor-binding state requires an extended interdomain hinge.

Arrestins selectively bind to the phosphorylated activated form of G protein-coupled receptors, thereby blocking further G protein activation. Structurally, arrestins consist of two domains topologically connected by a 12-residue long loop, which we term the "hinge" region. Both domains contain receptor-binding elements. The relative size and shape of arrestin and rhodopsin suggest that dramatic changes in arrestin conformation are required to bring all of its receptor-binding elements in contact with the cytoplasmic surface of the receptor. Here we use the visual arrestin/rhodopsin system to test the hypothesis that the transition of arrestin into its active receptor-binding state involves a movement of the two domains relative to each other that might be limited by the length of the hinge. We have introduced three insertions and 24 deletions in the hinge region and measured the binding of all of these mutants to light-activated phosphorylated (P-Rh*), dark phosphorylated (P-Rh), dark unphosphorylated (Rh), and light-activated unphosphorylated rhodopsin (Rh*). The addition of 1-3 extra residues to the hinge has no effect on arrestin function. In contrast, sequential elimination of 1-8 residues results in a progressive decrease in P-Rh* binding without changing arrestin selectivity for P-Rh*. These results suggest that there is a minimum length of the hinge region necessary for high affinity binding, consistent with the idea that the two domains move relative to each other in the process of arrestin transition into its active receptor-binding state. The same length of the hinge is also necessary for the binding of "constitutively active" arrestin mutants to P-Rh*, dark P-Rh, and Rh*, suggesting that the active (receptor-bound) arrestin conformation is essentially the same in both wild type and mutant forms.