Rheumatoid factors: good or bad for you?

BACKGROUND: Rheumatoid factors (RFs) are autoantibodies associated with rheumatoid arthritis. They can be detected in normal individuals, although transiently. This dichotomy has led to questions about the origins and types of RFs. Recently it has been shown that B cells that produce RFs only do so when activated by two signals, one from engagement of the B-cell receptor and the other from recognition of a pathogen-associated molecular pattern through a Toll-like receptor (TLR). These autoantibodies thus link the innate and acquired immune responses. OBJECTIVE: Through a review of the literature, an examination of the current knowledge of RF induction is presented. The focus is on a discussion of a beneficial or detrimental role for RFs in normal individuals and in those with chronic disease. RESULTS: What makes RF 'good' in some cases and 'bad' in others may reflect the type of RF produced. Low-affinity polyreactive IgM RFs are probably beneficial as they aid in the clearance of immune complexes that are more efficiently cleared, and the RF B cell can act as an antigen-presenting cell and stimulate host defense. However, large amounts of high-affinity RFs found in patients with chronic disease may be harmful by participation in a vicious cycle of autoantibody production by stimulation of self lymphocytes, and/or deposition in blood vessels thus causing vasculitis. CONCLUSIONS: Whether RFs are beneficial or detrimental depends on the context in which they are expressed, the type and amount of RF produced, whether the response is perpetuated by TLR ligation and whether other cells are stimulated either directly or indirectly by RF-positive B cells.     

Type 1 diabetes: lessons for other autoimmune diseases?

Type 1 diabetes (T1D) satisfies many of the criteria for an autoimmune disease. The impact of the environment to promote the development of T1D and the ability to identify individuals at risk for T1D years before clinical presentation afford lessons for other autoimmune diseases, in regard to gene-environment interactions and the potential for rational approaches to pre-clinical diagnosis and prevention. Public health measures aimed at the modern pro-inflammatory environment are required to stem the rising tide not only of T1D but other autoimmune and chronic inflammatory disorders. In the non-obese diabetic (NOD) model of spontaneous autoimmune diabetes, compelling evidence indicates that adaptive autoimmunity to the pancreatic beta cell is initially targeted against proinsulin. Proof-of-principle studies in the NOD mouse, which established that insulin and proinsulin peptides could be applied as tools to induce immune tolerance and protect against diabetes development, await successful translation to at-risk humans. Initial trials of insulin-specific immunotherapy in humans show promise and reveal ways of optimising this approach that are also applicable to other autoimmune diseases.     

Type 1 diabetes and viral infections: What is the relationship?

Type 1 diabetes (T1D) is the most common chronic metabolic disorder in children. Epigenetic and environmental factors capable of altering the penetrance of major susceptibility genes or capable of increasing the penetrance of low-risk genes are currently thought to play a role in triggering autoimmunity and T1D development. This paper discusses the current knowledge of the role of viruses in T1D. Most studies that have evaluated the potential association between viral infections and T1D have indicated that it is highly likely that some of these infectious agents play a role in T1D development. However, most T1D cases are immune-mediated, and it is supposed that the initial viral infection is capable of creating, in genetically predisposed subjects, a particular condition in which chronic local inflammation occurs through the persistence of the infecting virus in pancreatic tissue and the activation of autoimmunity by means of molecular mimicry, bystander activation, or both. Theoretically, this knowledge could lead to possible prophylaxis and therapy for T1D. Further studies devoted to evaluating which infectious agents are linked to T1D and which immune mechanisms induce or protect against the disease are needed before adequate prophylactic and therapeutic measures can be developed.     

Cytoplasmic droplets: the good, the bad or just confusing?

The term cytoplasmic droplets is used to mean two different structures by basic scientists and clinicians. The literature on the presence, position and loss of cytoplasmic droplets and their relationship to infertility in animal species is reviewed. It is proposed that a change in terminology is required: 'cytoplasmic droplet' should be used to describe normal droplets associated with functional sperm produced by normal spermatogenesis and 'excess residual cytoplasm' is suggested to describe abnormal droplets associated with dysfunctional sperm that are products of faulty spermatogenesis.     

Type 1 1/2 diabetes: myth or reality?

The disease process in classical Type 1 diabetes patients (IDDM) is believed to be autoimmune. In contrast, the disease process in classical Type 2 diabetes patients (NIDDM) is not autoimmune and a decreased sensitivity to insulin action is the main abnormality. The clinical distinction of Type 1 diabetes versus Type 2 diabetes is recognized to be imperfect and has limitations. There is a group of individuals (Type 1 1/2 diabetes), who present like typical NIDDM, but have some of the immunological and clinical features of IDDM. We review the current medical literature on Type 1 1/2 diabetes with special reference to its clinical characteristics, natural history and pathophysiology. Since the distinction between these two forms of diabetes may have important therapeutic implications especially with regards to the benefits of insulin therapy in patients with Type 1 1/2 diabetes and because of the need for uniformity in its diagnosis we recommend that both clinical plus biochemical criteria (the presence of ICA and/or GAD Ab, HLA typing and tests to quantify beta cell function) be used to make a diagnosis. Comparative studies in the area of cytokine production, T cell reactivity and autoantibody clustering between classic Type 1 diabetes and Type 1 1/2 diabetes patients are needed as are studies with the animal model of Type 1 1/2 diabetes, Psammomys obesus.     

Cytomegalovirus infection and development of allergic diseases in early childhood: interaction with EBV infection?

BACKGROUND: Chronic replication of cytomegalovirus and EBV in early life may affect the immune system and play a role in the development of allergy in children. OBJECTIVE: To assess the relation between cytomegalovirus infection and allergic disorders in children, including a possible interaction with EBV infection. METHODS: From a prospective birth cohort study in Stockholm, on factors of importance for development of allergy, 2581 four-year-old children were enrolled. The classification of allergic diseases was based on questionnaire answers and determination of IgE antibodies to common airborne and food allergens. IgG to cytomegalovirus was determined by a commercial ELISA and to EBV by indirect immunofluorescence. RESULTS: A total of 1191 (46%) children were cytomegalovirus-seropositive. There were no significant associations between seropositivity to cytomegalovirus and allergic manifestations, such as bronchial asthma, suspected allergic rhinitis, or atopic dermatitis. Seropositivity to cytomegalovirus alone, ie, without seropositivity to EBV, was related to IgE antibodies to airborne and food allergens (adjusted odds ratio, 1.8; 95% CI, 1.2-2.9). An antagonism between cytomegalovirus and EBV in relation to sensitization to airborne and food allergens was suggested ( P = .05). CONCLUSION: The study does not support the hypothesis that previous cytomegalovirus infection plays an important role in the pathogenesis of bronchial asthma, suspected allergic rhinitis, or atopic dermatitis in children. However, in the absence of EBV infection, cytomegalovirus infection may be related to sensitization to airborne and food allergens.     

The good,the bad,and the contingency: How patients’ treatment verification behaviors are linked to doctors’ reactions

ObjectiveThis article introducesTreatment Verification Behavior (TVB) to conceptualize patient proactivity. The article also aims to examine doctors’ responses to patients’ TVBs.MethodsA doctor-patient paired, two-wave data set was collected from eight hospitals in North China. We collected data from 304 doctor-patient dyads with each doctor rating, on average, three inpatients.ResultsThe results show that when patients consulted their doctors about information regarding a diagnosis or treatment (i.e.,consulting TVB), it improved doctors’ perception of the patients’ ability, which further increased doctors’ work engagement. Alternatively, when patients challenged doctors about information regarding a diagnosis or treatment (i.e., challenging TVB), it induced doctors’ perception of threat but without significantly decreasing doctors’ work engagement. In addition, when doctors felt respected by patients, this feeling moderated the effects of patients’ TVBs on doctors’ reactions.ConclusionBoth the content (the “what”) and the manner (the “how”) of patients’ proactive communications with their doctors will influence doctors’ responses.Practice implicationsThese insights suggest that patient and doctor communication training should include components that address both the content and performance of communication.     

Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?

Background

The 2′,5′‐oligoadenylate synthetase genes (OAS1, OAS2, and OAS3) map to human chromosome 12q24 and encode a family of enzymes pivotal to innate antiviral defence. Recently, the minor allele of an OAS1 single nucleotide polymorphism (SNP) that alters splicing (rs10774671) was found to be associated with increased enzymatic activity and, in a case‐sibling control study, with type 1 diabetes (T1D).

Methods

We have confirmed this T1D association in 784 nuclear families (two parents and at least one affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other two OAS genes, functional attribution of the association to this SNP cannot be assumed. To help answer this question, we also genotyped two non‐synonymous SNPs in OAS1 exons 3 and 7.

Results

All three SNPs showed significant transmission distortion. Three of the eight possible haplotypes accounted for 98.4% of parental chromosomes and two of them carried the non‐predisposing A allele at rs10774671. Parents heterozygous for these two haplotypes showed significant transmission distortion (p = 0.009) despite being homozygous at rs10774671.

Conclusions

We confirm the T1D association with rs10774671, but we conclude that it cannot be attributed (solely) to the splicing variant rs10774671. A serine/glycine substitution in OAS1 exon 3 is more likely a functional variant.     

Rumination and cigarette smoking: a bad combination for depressive outcomes?

Ruminative coping has been shown to heighten the risk and severity of depression. The authors hypothesized that ruminators who smoke would experience greater depressive symptoms than ruminators who do not. The rationale is that, by heightening attentional focus, nicotine may increase ruminators' ability to focus on negative thoughts, augmenting depressed mood. Participants (N = 145) self-reported smoking status, rumination, and current and lifetime depressive symptoms, including depressed mood. Results showed that rumination accounted for a larger amount of variance in current and past depressed mood and severity of lifetime depressive symptoms among smokers than nonsmokers. Noncorrelational, experimental research should directly test whether nicotine worsens depressed mood among ruminative smokers. Such evidence would be surprising because it would contradict the assumption that nicotine dispels negative moods.     

Combination of monoclonal antibodies and DPP-IV inhibitors in the treatment of type 1 diabetes: A plausible treatment modality?

Regulatory T cells (Tregs) are crucial for the maintenance of immunological tolerance. Type 1 diabetes (T1D) occurs when the immune-regulatory mechanism fails. In fact, T1D is reversed by islet transplantation but is associated with hostile effects of persistent immune suppression. T1D is believed to be dependent on the activation of type-1 helper T (Th1) cells. Immune tolerance is liable for the activation of the Th1 cells. The important role of Th1 cells in pathology of T1D entails the depletion of CD4⁺ T cells, which initiated the use of monoclonal antibodies (mAbs) against CD4⁺ T cells to interfere with induction of T1D. Prevention of autoimmunity is not only a step forward for the treatment of T1D, but could also restore the β-cell mass. Glucagon-like peptide (GLP)-1 stimulates β-cell proliferation and also has anti-apoptotic effects on them. However, the potential use of GLP-1 as a possible method to restore pancreatic β-cells is limited due to rapid degradation by dipeptidyl peptidase (DPP)-IV. We hypothesize that treatment with combination of CD4 mAbs and DPP-IV inhibitors could prevent/reverse T1D. CD4 mAbs have the ability to induce immune tolerance, thereby arresting further progression of T1D; DPP-IV inhibitors have the capability to regenerate the β-cell mass. Consequently, the combination of CD4 mAbs and DPP-IV inhibitor could avoid or at least minimize the constraints of intensive subcutaneous insulin therapy. We presume that if this hypothesis proves correct, it may become one of the plausible therapeutic options for T1D.     

Protection against or triggering of Type 1 diabetes? Different roles for viral infections

The emergence of autoreactivity that ultimately destroys insulin-producing β-cells and causes Type 1 diabetes (T1D) is a result of genetic susceptibility and environmental factors, such as viral infections. The ability to induce strong cellular immune responses and to cause inflammation in the target organ makes viral infections prime candidates for the initiation of islet autoreactivity. Indeed, certain viruses have been linked to the occurrence of T1D based on epidemiological, serological and histological findings; and several rodent studies clearly demonstrate that viral infections can trigger autoimmunity. However, viruses have also been shown to efficiently prevent autoimmunity, which underlines the beneficial aspects of exposure to microbial agents as suggested by the hygiene hypothesis. Here, we will try to untangle some aspects of the complex interplay between viruses and the immune system and we will recapitulate by what rationale certain viruses have been associated with T1D.