Clinical and applied immunology reviews最新文献

Eosinophilic esophagitis is a newly described clinicopathologic entity that is being diagnosed with increasing frequency. Although accepted diagnostic criteria have not been established, the presence of dense eosinophilic inflammation of esophageal mucosa are key. Because of the reflux-type symptomatology, it is commonly misdiagnosed and treated as severe gastroesophageal reflux disease before an appropriate diagnosis is made. The role of food allergens in this disorder is well accepted but the task of identifying specific antigens remains a clinical challenge. Based on animal studies, the pathophysiology appears to involve inflammatory cytokines, interleukin 5 (IL-5) and eotaxin. Therapy remains problematic because of steroid side effects, the unpalatability of the elemental diet, and lack of rigorously designed trials.

It is well known that neonatal immune function is immature compared to adults and that ontogeny of the immune system continues for some time postnatally. This renders infants particularly susceptible to pulmonary bacterial and viral infections often associated with childhood. Innate immune responses are less intense and delayed compared to adults. Antigen presentation is immature in that antigen presenting cells are slow in upregulating costimulatory molecules. This results in reduced T-cell responses including T-cell help and cytotoxic lymphocytes (CTL) function. B-cell responses suffer from the lack of T-cell help. The maturation process of immune mediators in newborns corresponds with postnatal development of the lungs and may be a mechanism that keeps inflammation from causing damage to developing lungs.

Inexpensive antiretroviral therapy (ART) might soon be available to treat human immunodeficiency virus (HIV) infections in resource-restricted areas of the globe. The number of CD4+ T-cells in the blood is the single most important laboratory parameter to select patients for therapy at the right time and to monitor the effect of ART. The question is asked whether flow cytometry is adaptable to change from an expensive and complicated scientific analytical instrumentation to become a practical diagnostic tool that can be widely operated. Recent studies indicate that a branch of clinical/practical flow cytometry is gaining a new identity by a confident simplification and improvement of clinical protocols. These new observations can be marshaled into three new areas of development. First, the changes in the choices of reagents and staining protocols have been initiated by the preferred use of primary immunological gating during the flow-cytometric analysis, exploiting the exquisite discriminating power of antibodies. The recent National Institutes of Health (NIH) and Centers for Disease Control and Prevention (CDC) guidelines introduced CD45-assisted protocols that are also at the heart of the PanLeucogating protocol that revitalized the testing of absolute CD4 counts on double-platform. With CD45 staining the leucocyte populations can be reliably studied in aging samples. It is now also documented that minimal technology, that is primary gating with CD4 (or CD8) antibodies, provides excellent CD4 (or CD8) T-cell counts. Consequently the optimal affordable protocol uses CD45 and CD4 antibodies in combination. The second area of development is the absolute counting facility on flow cytometers. Most frequently, microbeads are added to blood to define the sample volume in instruments that are not equipped with a volumetric microsyringe. The beads are, however, expensive, and the utilization of the stable flow rate of the excellent instruments might soon provide an answer to replace dear microbeads. With stable flow, the time span of analysis tells the sample volume and the absolute counts can be calculated. Finally, stabilized blood cell standards and blood stabilizing fluid, referred to as Transfix, have recently been introduced for quality assurance. These products are important to prove the precision and accuracy of the new affordable protocols and also to check, and guide if necessary, the performance of the laboratories even in remote areas. These recent developments provide evidence about the renaissance of affordable flow cytometry, a precise, costeffective and quantitative technology that is capable of providing CD4+ T-lymphocyte counts in as high volume as >400 patient assessment per day at the fraction of the cost of the current Western prices. These recent achievements need to be taken into consideration when alternative, nonflow CD4-counting methods are assessed.

The antiphospholipid antibody syndrome (APS) is the association of certain clinical features with the presence of antiphospholipid antibodies (APA) in the serum or plasma of affected individuals. APS may be primary or secondary to another disease, typically autoimmune diseases such as systemic lupus erythematosus (SLE).

The prototypic clinical features are thrombotic events (venous and arterial) and pregnancy morbidity (recurrent fetal loss, severe preeclampsia, eclampsia, and multiple spontaneous abortions). The term antiphospholipid antibody is a misnomer since it now appears that APA are actually directed against protein phospholipid complexes. APA may also occur secondary to infections however these APA seem to be directed at phopsholipid only and are transient. Particular phospholipid-binding proteins associated with APS include beta 2-glycoprotein I (B2GPI), prothrombin, and annexin V. A recent International Consensus Statement defines Definite APS as the presence of certain clinical findings (either a thrombotic event and/or pregnancy morbidity) and the presence and persistence of laboratory evidence of APA [either the lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACL)]. Other clinical features associated with APS include thrombocytopenia, various skin conditions, cardiac valvular diseases, and diverse neurological conditions as outlined in the main text. These other features may be part of APS but require further evidence to establish their pathological and clinical validity. Other laboratory tests of interest include anti-B2GPI, antiprothrombin, and antiphosphatidylserine antibodies. The diagnostic and clinical importance of these additional laboratory tests remains to be determined.

APA are estimated to be present in up to 5% of the general population, with the prevalence increasing with age. APA are estimated to be present in 12% or more of patients with thrombosis. ACL are present in 12 to 30% of patients with SLE and LA are present in 15 to 34% of patients with SLE. There is often concordance between LA and ACL however this is not always true. APA (both ACL and LA) are associated with thromboembolic events. Venous thrombosis is more common than arterial thrombosis and a minority of patients have both. LA is more strongly associated with thrombosis than ACL. The estimated yearly incidence of thrombosis in individuals with APA is 1% for those with no history of thrombosis, 4% for those with SLE, and 6% for those with high titer immunoglobulin G (IgG) ACL. The presence of LA, and possibly of medium to high titers of IgG ACL, help identify patients at risk for thrombosis.

Progress in the detection and quantitation of autoantibodies associated with rheumatoid arthritis (RA) indicates an expanding role for serology in the diagnosis and predicting the prognosis of the disease. The advent of enzyme-linked immunoadsorbant assay (ELISA) methods for the quantitation of rheumatoid factor (RF) isotypes offers significant RA disease information substantially above that gained using traditional measurements of total RF. The ability to quantitate isotypes adds specificity for the diagnosis of RA and identifies those individuals that will tend to exhibit progressive, erosive disease. Other autoantibodies that are highly specific for RA recognize epitopes associated with proteins containing citrulline (e.g., antikeratin and antiperinuclear factor). A highly specific (92–98%) and relatively sensitive (∼80%) second-generation ELISA has been developed and marketed for the diagnosis of RA using cyclic citrullinated peptide as antigen (CCP). Population based studies indicate that finding multiple RF isotypes or antifilaggrin antibodies (synonymous with anti-CCP) in apparently normal individuals is highly predictive for the development of RA in subsequent years. More importantly, these markers are being recognized as indicative of disease course. Monitoring C-reactive protein and erythrocyte sedimentation rate continue to be a mainstay for determining RA disease activity, although acute-serum amyloid A may be a more sensitive marker for synovial inflammation.

Immune-based therapies can be broadly divided into strategies aimed toward amplifying beneficial immune responses or attenuating harmful responses, which induce tissue damage to autologous tissues. Interleukin-7 (IL7) holds promise as an immunotherapeutic because of its potent capacity to amplify T-cell based immunity. Its requirement for thymopoiesis and evidence in murine models showing that thymic emigrants are increased when IL7 is administered following bone marrow transplant have led to the hypothesis that IL7 might be able to enhance immune reconstitution following disease and/or therapy induced T-cell depletion. In addition, the IL7 receptor is expressed on most mature CD4+ and CD8+ T-cells and signaling through this receptor can accentuate responses to cognate antigen and induce T-cell activation toward weak antigens. As a result, supraphysiologic levels of IL7 induce widespread peripheral T-cell cycling. Thus, IL7's effects on mature T-cells would be expected to improve overall immune competence in T-cell depleted hosts and may allow IL7 to enhance the therapeutic benefit of antiviral and/or antitumor vaccines.

P-glycoprotein (P-gp) is a member of adenosine triphosphate (ATP)-binding cassette transporter superfamily that is expressed in a variety of hematopoietic cells. Although a role of P-gp in multidrug resistance in cancer is well-established, its physiological role in immune cells remains unclear. A role for P-gp in the secretion of cytokines and in cytotoxic effector functions has been suggested; however, knock out experiments suggest that P-gp may not be required for cytokine secretion or effector functions. There is no linear correlation between the expression of P-gp and hyporesponsiveness to antigens in aging. A recently discovered role of P-gp in T-cell survival has been discussed in the context of the aging process. A functional role for P-gp in the context of aging of memory subsets of CD4+ and CD8+ T-cells remains to be investigated. The use of a combination of P-gp expression and efflux of substrate dyes in the presence or absence of modulators of P-gp function to determine the structure-functional relationship and some of the limitations in the use of efflux of fluorescent dyes alone as a measure of the expression of P-gp have been reviewed.