Post-translational control of chemokines: a role for decoy receptors?

It is well-established that chemokines play a critical role in the orchestration of inflammation and immunity. Interactions between chemokines and their receptors are essential for the homing of specific subsets of leukocytes to their functional microenvironments. They also influence other diverse biological processes such as development, leukocyte activation, Th1/Th2 polarisation, tumour metastasis, angiogenesis, and HIV pathogenesis. However, despite their importance, only now are we beginning to understand the complex regulation brought to bear on these molecules. In this review, we discuss a number of these key chemokine regulators that exert their influence once these proteins have been synthesised. We examine (i) chemokine storage, release, and presentation, (ii) protease regulation, (iii) viral manipulation of host chemokines, and (iv) natural mammalian receptor antagonists. Principally, the growing evidence for a role for decoy receptors in the chemokine system is discussed. In particular, the potential decoy function of the 'silent' pro-inflammatory chemokine receptor D6 is described alongside two other candidate decoy receptor molecules, DARC, and CCX-CKR. Dissecting the biological and pathological function of these chemokine controllers will lead to a deeper understanding of chemokine regulation, and may reveal novel strategies to therapeutically modify the chemokine system.     

Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens?

Psoriasis is a T-cell-mediated disease that can be triggered by infection with group A β-haemolytic streptococci. It is proposed that psoriatic skin lesions are initiated by exotoxin-activated T cells, and persist because of specific T cells that react both with streptococcal M protein and a skin determinant, possibly a variant of keratin. As discussed here by Helgi Valdimarsson and colleagues, cytokines released by the superantigen (SAg)-stimulated T cells could induce or enhance the expression of the crossreactive autoantigen, leading to the rescue and activation of autoreactive T cells. In this way, the SAg-determined T-cell receptor Vβ phenotype would be maintained by T cells in psoriatic lesions.     

Cellular adequacy for thyroid aspirates prepared by ThinPrep: How many cells are needed?

Although it is well established that ThinPrep introduces artifacts to thyroid aspirates, no criteria have been established for adequacy of such specimens. This study evaluates the adequate number of cells needed to establish the correct diagnosis based on ThinPrep alone. A total of 218 thyroid aspirates prepared by TP with surgical pathology follow-up were reviewed. The cellularity was calculated as follows: Count the total number of clusters, randomly select 10 clusters and count each, calculate the average number per cluster and multiply by the total number of clusters. A minimum number of 6 clusters with 10 cells each was arbitrary established to assume adequacy for a definitive diagnosis. Cytologic diagnoses were classified as: Nondiagnostic (ND), cystic contents, thyroiditis, nodular hyperplasia (NH), follicular/Hurthle (F/H) cell lesion, F/H cell neoplasm, and carcinoma: qualify. Histologic diagnoses were classified as: Cyst (colloid or otherwise), thyroiditis, NH, F/H adenoma, F/H carcinoma, carcinoma: qualify. Appropriate treatment triage was considered to be clinical for the former 4 cytologic categories and surgical for the latter 3 with ND warranting repeat aspiration. The results were subjected to logistic regressions analysis and contingency tables correlating the number of cells with the cytologic and histologic diagnosis as well as with treatment triage. Cellularity of sample was ranked in 10 deciles according to the number of cells and in 4 quartiles according to the number of clusters. The agreement percentage, for both diagnostic and treatment, was computed for each decile and quartile. 146 (67%) cases had cells and received a diagnosis while 72 (33%) were acellular. Of the 146 cases, 21 contained histiocytes or colloid only. 91/146 (62.3%) were correctly diagnosed and 123/146 (84.3%) would have been correctly triaged for treatment based upon the cytologic diagnosis. Samples with 180 cells or fewer had an agreement rate below 50%. Agreement rate increases to 80% when cellularity is 180-320. Above 320 agreement rate remains high but not uniformly. Total number of clusters did not play an independent role and only the number of cells per cluster had a significant correlation with diagnostic agreement. A 25-cell increase in average cells per cluster increases the odds of agreement between diagnoses by 65%.     

The composition of intrahepatic lymphocytes: shaped by selective recruitment?

Intrahepatic lymphocytes have a distinct subset composition and phenotype. Compared with lymphoid tissues, the frequency of natural killer (NK) cells, NKT cells and gammadelta T cells among total lymphocytes is increased within the liver, and alphabeta T cells are predominantly effector/memory cells. Divergent hypotheses on the origin of intrahepatic T cells have emerged to explain this; in these hypotheses, either local development or selective recruitment of cells into the liver dominates. This Opinion highlights findings showing that the migratory preferences of lymphocyte subsets reflect their representation within the liver surprisingly well, suggesting that the composition of intrahepatic lymphocytes, in the absence of inflammation, is largely shaped by the dynamics of cell entry and exit into and from the liver.     

Hyperosmolar induced histamine release from mast cells: A mechanism for the pathogenesis of exercise-induced asthma?

Hyperosmolar buffer solutions produced by the addition of mannitol (0.1–1.0M) induced histamine release from mast cells from dispersed human lung (DL), bronchoalveolar lavage (BAL) and the rat peritoneal cavity (RPMC). The maximal releases wereca 60% (RPMC), 40% (BAL) and 15% (DL), respectively.Under defined conditions, the release from the RPMC was shown to be non-cytotoxic with biphasic kinetics. The process was inhibited by disodium cromoglycate, nedocromil sodium and theophylline, with IC₅₀ values ofca 100 M, 100 M and greater than 10 mM, respectively. On the basis of these results, the role of hyperosmolar induced mast cell activation in exercise-induced asthma is discussed.     

Is ATP-sensitive K+ channel (K+ATP) recruitment a common mechanism for ECG-ST segment depression and elevation?

ATP sensitive (K(+)(ATP)) potassium cardiac channels are recruited when ATP levels are low as in ischemic injury and acute trauma. Such activation results in ECG-ST elevation and cardiac arrhythmias. K(+)(ATP) channel recruitment may be blocked by the sulfonylurea glibenclamide, permitting a wide variety of animal experimentation designed to test the genesis of ECG-ST segment elevations and depressions in diverse conditions including digitalis effect, acute arterial occlusion, tachycardias, and acute pericarditis. A specific series of animal experiments designed to test this hypothesis is proposed. Clinical implications are discussed.     

Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity?

Patterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.     

Glycogenosis type I and diabetes mellitus: a common mechanism for renal dysfunction?

Diabetes mellitus and glycogen storage disease type I (GSDI) may initially appear disparate in metabolic profile: one characterized by uncontrolled hyperglycaemia due to disturbed insulin function and the other by fasting hypoglycaemia caused by impaired gluconeogenesis and glycogenolysis. However, they share a remarkably similar pattern and progression of renal dysfunction. This may be, we suggest, due to a convergence of their metabolic sequelae in upregulation of flux through the pentose phosphate pathway. This pathway yields triose phosphate molecules, which are precursors of the lipid, diacylglycerol (DAG). DAG plays an important role in the intrarenal renin-angiotensin system via the protein kinase C pathway. GSDI may be an interesting model which helps to unravel further the contributions of the many, varied nephropathic influences in diabetes. Conversely patients with this rare disorders would have much to gain from the innovative and vastly greater body of research carried out in diabetes.     

Hepatitis-like syndrome induced by nimesulide?

The authors describe a case report of a 17 years old woman, complaining of weakness and malaise, associated with a significant increase of serum transaminases, that occurred twice in a month soon after the administration of Nimesulide per o.s.     

Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen‐activated protein kinase (Ras/MAPK) pathway components. Cardio‐facio‐cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor‐stimulated fibroblasts revealed that P‐MEK1/2 was ～50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.     

Hyaluronan cross-linking: a protective mechanism in inflammation?

Production of the glycosaminoglycan hyaluronan is increased at sites of inflammation, often correlating with the accumulation of leukocytes. Mounting evidence suggests that this polysaccharide can be organized into a wide variety of molecular architectures by its association with specific binding proteins, leading to the formation of fibrils and cable-like structures involving a large number of hyaluronan chains. We propose that hyaluronan cross-linking is part of a protective mechanism, promoting adhesion of leukocytes to the hyaluronan complexes rather than enabling contact with inflammation-promoting receptors on the underlying tissues. Leukocytes are thus maintained in a non-activated state by appropriate receptor clustering or receptor co-engagement. Additionally, hyaluronan networks might serve as scaffolds to prevent the loss of extracellular matrix components during inflammation and to sequester proinflammatory mediators.     

Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines?

Cell migration is crucial for intrathymic T-cell differentiation. Chemokines and extracellular matrix proteins per se induce thymocyte migration, and recent data suggest a combinatorial role for these molecules in this event. For example, thymocyte migration induced by fibronectin plus CXCL12/SDF1-alpha (stromal cell-derived factor1-alpha) is higher than that elicited by the chemokine alone. If such interactions are relevant in the thymus, abnormal expression of any of these ligands and/or their corresponding receptors will lead to defects in thymocyte migration. At least in the murine model of Chagas disease, this seems to be the case. Therefore a better knowledge of this complex biological circuitry will provide new clues for understanding thymus physiology and designing therapeutic strategies targeting developing T cells.