Human leukocyte antigens (HLA) associated drug hypersensitivity: consequences of drug binding to HLA

Recent publications have shown that certain human leukocyte antigen (HLA) alleles are strongly associated with hypersensitivity to particular drugs. As HLA molecules are a critical element in T‐cell stimulation, it is no surprise that particular HLA alleles have a direct functional role in the pathogenesis of drug hypersensitivity. In this context, a direct interaction of the relevant drug with HLA molecules as described by the p‐i concept appears to be more relevant than presentation of hapten‐modified peptides. In some HLA‐associated drug hypersensitivity reactions, the presence of a risk allele is a necessary but incomplete factor for disease development. In carbamazepine and HLA‐B*15:02, certain T‐cell receptor (TCR) repertoires are required for immune activation. This additional requirement may be one of the ‘missing links’ in explaining why most individuals carrying this allele can tolerate the drug. In contrast, abacavir generates polyclonal T‐cell response by interacting specifically with HLA‐B*57:01 molecules. T cell stimulation may be due to presentation of abacavir or of altered peptides. While the presence of HLA‐B*58:01 allele substantially increases the risk of allopurinol hypersensitivity, it is not an absolute requirement, suggesting that other factors also play an important role. In summary, drug hypersensitivity is the end result of a drug interaction with certain HLA molecules and TCRs, the sum of which determines whether the ensuing immune response is going to be harmful or not.     

Human leukocyte antigens as psoriasis inheritance and susceptibility markers

Psoriasis is a multifactoral and heterogenetically inherited disease. The role of hereditary transmission is supported by familial association, twin studies, and correlation with human leukocyte antigens (HLA). Numerous studies have proved that B13, B17, Cw6, and DR7 antigens are positively associated with psoriasis. Cw6 antigen has been repeatedly indicated to be the most significant marker for the risk prediction of the disease. On the basis of epidemiological studies and HLA analysis, a concept of two distinct disease patterns of psoriasis vulgaris was proposed. In type I psoriasis the disease has an early onset, strong correlation with Cw6, B13, B17, and DR7 antigens, and familiar inheritance. Type II psoriasis has a late onset, weak correlation with HLA antigens, and sporadic familiar occurrence. Both types seem to differ clinically. Moreover, some extended haplotypes were shown to be correlated with the disease, especially with the type I psoriasis. Although a psoriasis susceptibility gene(s) has not been yet identified, a number of candidate genes were studied, with evidence for a major locus located within the major histocompatibility complex (PSORS 1). Cw6 allele is the most extensively investigated candidate gene, but present evidence suggests that it is rather in strong linkage disequilibrium with the PSORS 1 gene than the susceptibility allele itself. This article reviews past and current data on the genetic background of psoriasis with special attention to its correlation with HLA antigens.     

Human leukocyte function-associated antigens on lympho-hemopoietic precursor cells

The expression of human leukocyte function-associated antigens (HLFA, equivalents of murine LFA-1) was studied on early lympho-hemopoietic cells in infant thymus and normal bone marrow by double immunofluorescence methods, cell sorting and colony-forming assays. Monoclonal antibodies MHM-24 recognizing the alpha chain (180 kDa) and 60.3 and 60.1 identifying the beta chain (95 kDa) were used. The vast majority of thymocytes including large terminal deoxynucleotidyl transferase (TdT)-positive blast cells are HLFA positive. On the other hand, most B cell precursors in the bone marrow, identified by the expression of nuclear TdT, do not show surface HLFA which appears at the pre-B cell stage (cytoplasmic mu positive, surface Ig negative). Cell sorting experiments revealed an enrichment of early myeloid cells (myeloblasts and colony-forming unit cells) in the HLFA-negative fraction. Erythroid cells appeared to be completely negative from the burst-forming unit erythrocyte stage onwards. Anti-HLFA-antibodies, capable of blocking T cell and natural killer function, may have therapeutic potential without interfering with precursor cell development in man.     

Human leukocyte antigen association with azathioprine-induced drug hypersensitivity reactions in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Azathioprine (AZA) drug hypersensitivity reaction (DHR) is an uncommon yet potentially lethal condition that often goes unrecognised in patients with anti-Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV). We conducted a retrospective review of AAV patients on AZA maintenance therapy (N = 35). Participants were categorised into those who had experienced AZA-DHR (N = 15) and those who were AZA-tolerant (N = 20). Human leukocyte antigen (HLA) typing was performed in both groups. The primary endpoint was identification of a HLA gene association with AZA-DHR in the context of AAV. HLA-C*06:02, was solely expressed in AZA-DHR patients (33.3 %), whilst no patient who tolerated AZA carried this allele (0.0 %). This yielded a positive predictive value of 100 % for HLA-C*06:02 in predicting AZA-DHR in AAV patients, negative predictive value of 66.7 %, sensitivity of 33.3 % and specificity of 100 %. HLA-C*06:02 may predict the development of AZA-DHR in patients with AAV and inform safer therapeutic choice.     

Human leukocyte antigens: an update on structure, function and nomenclature

The study of human leukocyte antigens, predominantly by monoclonal antibody techniques, is a rapidly changing area of basic research and clinical investigation. This review outlines some of the results and trends of research in this field. Of particular importance is the updating of the current nomenclature. The CD classification of these antigens has become the standard form in published literature and provides a basis for standardization of clinical reporting. The current CD classification is presented in the form of a list, with a brief summary of each antigen beside each entry. The results reviewed range from the section on CD1 antigen in which the data presented are primarily concerned with the underlying biology of the antigens to the section on clinical application which has little biological content.     

Viral infections and drug hypersensitivity

Virus infections and T-cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i): drugs tend to bind to proteins and may even bind to immune receptors. Without viral infections, this low affine binding may be insufficient to elicit T-cell activation. During a viral infection, immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p-i reactions and may even be sufficient for T-cell activation and symptoms. There is a situation where the virus-DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p-i mediated immune stimulation during acute DRESS, which coincidentally activates many herpes virus-specific T cells. Through p-i stimulation, they develop a cytotoxic activity by killing herpes peptide-expressing cells and releasing herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes-virus viraemia after DRESS.     

Human leukocyte elastase

This article reviews some properties of human leucocyte elastase. This 30 kDa glycoprotein formed of 218 amino acid residues, is a serine proteinase which cleaves proteins at Val-X, Ala-X, Leu-X or Met-X bonds. Leucocyte elastase solubilizes fibrous elastin and also degrades other extracellular matrix proteins. It hydrolyses and inactivates a number of plasma proteins. Synthetic substrates are more convenient than elastin to measure elastase activity. A large number of natural and synthetic inhibitors of leucocyte elastase have been described. The former include alpha 1-proteinase inhibitor or alpha 1-antitrypsin, inter-alpha-inhibitor, alpha 2-macroglobulin, bronchial and cervical mucous inhibitor and a number of animal and plant proteins. Numerous synthetic inhibitors with therapeutic potentials have been designed. The efficiency of an inhibitor depends, among others, upon its rate of association with the enzyme and upon the stability of the enzyme-inhibitor complex. Elastase probably plays a physiological function in neutrophil migration, phagocytosis and tissue remodeling. It apparently plays a pathological role in pulmonary emphysema, rheumatoid arthritis, infections and inflammation. The pathogenic role of leucocyte elastase is best understood in emphysema.     

Characterization of swine leukocyte differentiation antigens

The First International Swine CD Workshop summary meeting was held in Budapest, Hungary, on August 16, 1992, as a satellite to the Third International Veterinary Immunology Symposium. The workshop which was supported by the Veterinary Immunology Committee of the International Union of Immunological Scientists was divided into sections: T cells, activation antigens, B cells, macrophages/granulocytes, null cells, CD44/45 and data management.     

Characterization of swine leukocyte differentiation antigens

There is considerable interest in the porcine immune system, particularly because of the physiological similarity of swine and humans. The aim of a recent meeting^*     

Aspirin and nonsteroidal anti-inflammatory drug hypersensitivity

Acetylsalicylic acid (ASA) or aspirin and nonsteroidal anti-inflammatory drug (NSAID) sensitivities encompass a diverse group of both pharmacological and hypersensitivity reactions. Conventionally, hypersensitivities include aspirin-exacerbated respiratory disease (AERD), ASA-induced urticaria, and anaphylaxis. With an increasing prevalence of coronary artery disease in an aging population, aspirin continues to play a significant role in cardiac prophylaxis in a large patient population. Invariably, the clinician will encounter patients with clear indications for aspirin therapy but a history of aspirin sensitivity. Although protocols have been established for aspirin challenge and desensitization, it is not always an efficacious or safe procedure. This article reviews the different classifications of ASA/NSAIDs hypersensitivities to better guide the clinician in dealing with this patient population. History of crossrelativities between multiple NSAIDs implies a non-IgE-mediated process. Similarly, a history of monosensitivity to one NSAID implies an IgE-mediated process, although specific antibodies are often elusive. Despite the name, AERD can potentially be exacerbated by all cyclooxygenase (COX) inhibitors based on dose-dependent inhibition of COX-1. Aspirin desensitization can be achieved to improve both upper and lower respiratory symptoms for most patient with AERD. Aspirin desensitization can usually be achieved for those in need of the antiplatelet effects of aspirin, with the exception of those with aspirin-induced urticaria and baseline chronic urticaria. However, desensitization should only be attempted in those with stable coronary artery disease because the process of desensitization carries the inherent risk of anaphylaxis/anaphylactoid reaction, which may further increase cardiac demand and bring about ischemic injury. Therefore, desensitization is reserved until coronary artery disease is stabilized.     

可溶性人类白细胞抗原的研究进展与临床应用

可溶性人类白细胞抗原(sHLA)是存在于人类血清或其它体液中的HLA可溶性形式.近十年的研究显示sHLA在医学上意义重大.因其可参与调节免疫应答和诱导免疫耐受而被普遍重视,在器官移植、感染性疾病、肿瘤、自身免疫性疾病等病理状态下,血清中sHLA的含量均有明显变化.