Autoantibodies with enzymatic properties in human autoimmune diseases

Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino acid residues by N-linked glycosylation and occasionally by O-linked glycosylation. The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation with activation of complement and activation of effector cells. In addition to this plethora of functions, some antibodies express enzymatic activity. Antibodies endowed with enzymatic properties have been described in human autoimmune manifestations in a variety of disorders such as autoimmune thyroiditis, systemic erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), multiple sclerosis (MS) and acquired hemophilia (AH). Antibodies isolated from these conditions were able to specifically hydrolyze thyroglobulin, DNA, RNA, myelin basic protein (MBP), and factor VIII (FVIII) or factor IX (FIX), respectively. The therapeutic relevance of these findings is discussed.     

A retrospective analysis of facial fracture etiologies

The medical records of 437 patients with 929 facial fractures were retrospectively analyzed. Fracture patterns were classified based on the presence or absence of fractures in each of 4 anatomic subunits (frontal, upper midface, lower midface, and mandible). The most common etiology of trauma was assault (36%), followed by motor vehicle collision (MVC, 32%), fall (18%), sports (11%), occupational (3%), and gunshot wound (GSW, 2%). The most common fracture type was nasal bone fracture (164). MVC was found to be a significant predictor of panfacial fractures, as was GSW. Sports injuries were a significant predictor of isolated upper midface fractures, and assault was a significant predictor for isolated mandible fractures. MVC and GSW each were found to lead to significantly higher severity of injury than assault, fall, and sports. The results confirm intuitive aspects of the etiology of facial fractures that have been anecdotally supported in the past.     

B cells are resistant to immunomodulation by 'IVIg-educated' dendritic cells

Intravenous immunoglobulin (IVIg) can exert beneficial effects in autoimmune and inflammatory diseases via several mutually non-exclusive mechanisms. While, IVIg can directly modulate the functions of both innate and adaptive immune cells such as dendritic cells (DC), macrophages, B and T cells, several reports have also highlighted that the regulation of immune responses by IVIg can be indirect. In view of these results, we aimed at exploring whether indirect regulation of immune cells by 'IVIg-educated' innate cells is a universal phenomenon. We addressed this question by deciphering the modulation of B cell functions by 'IVIg-educated' DC. Our results indicate that human B cells are resistant to immunomodulation by 'IVIg-educated' DC. However, IVIg at therapeutic concentrations can directly inhibit B cell activation and proliferation. These results thus suggest that, indirect modulation of immune cells by IVIg is not a universal phenomenon.     

Drug resistant tuberculosis in diabetes mellitus: a retrospective study from south India

This study was conducted in a tertiary care teaching hospital in south India to evaluate the association of drug resistant tuberculosis (TB) in diabetic subjects. There were: 361 subjects with positive mycobacterial culture and susceptibility tests results over a 3-year period; 267 (74%) acid-fast bacillus smear positive; and 94 (26%) smear negative cases. One hundred and seventy-seven (49%) had resistant isolates to any one first line antiTB drugs (resistant group) and 184 (51%) had isolates sensitive to all drugs (non-resistant group). In the resistant and non-resistant subjects the mean duration of TB symptoms was, respectively, 22 months and 4.5 months, past history of TB 126 (71%) and 48 (26%), past antiTB drug therapy 126 (71%) and 47 (25%), inadequate anti TB drug therapy 42 (24%) and 23 (13%), HIV positive six and 13 subjects. There were 72 diabetic subjects [35 and 37, respectively] with a duration of diabetes 5.8 +/- 7.5 years and 3.7 +/- 5.0 years in the resistant and non-resistant groups. Twenty-six per cent of the diabetic subjects (19/72) had multi-drug resistantTB. Drug resistance to first line anti-TB drugs was not found to be associated with diagnosis or duration of diabetes mellitus.     

Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin

Normal immunoglobulin G for therapeutic use (intravenous immunoglobulin [IVIg]) is used in an increasing number of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIg. Although IVIg inhibits T-cell proliferation and T-cell cytokine production, it is unclear whether these effects are directly dependent on the effects of IVIg on T cells or they are dependent through the inhibition of antigen-presenting cell activity. Here, we examined the effects of IVIg on differentiation, maturation, and function of dendritic cells (DCs). We show that IVIg inhibits the differentiation and maturation of DCs in vitro and abrogates the capacity of mature DC to secrete interleukin-12 (IL-12) on activation while enhancing IL-10 production. IVIg-induced down-regulation of costimulatory molecules associated with modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T-cell activation and proliferation. Modulation of DC maturation and function by IVIg is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.     

Prospects for disease modification in osteoarthritis

Osteoarthritis (OA) can be a progressive, disabling disease, leading to diminished quality of life, and, for over 500,000 individuals annually in the US, total joint replacement. The etiology of OA will vary among individuals, with potential roles for systemic factors (such as genetics and obesity) as well as for local biomechanical factors (such as muscle weakness, joint laxity and traumatic injury). Joint deterioration occurs over extended periods of time, and the diverse molecular mechanisms that mediate pathogenic events of early, mid and late disease are not yet fully understood. The success of biologic therapies in the treatment of rheumatoid arthritis has demonstrated that the blockade of a single dominant cytokine or regulatory molecule can prevent cartilage destruction in a complex disease, and has raised expectations that mechanism-based treatments could also be developed for patients with OA. In this review, we will address the biological mechanisms that mediate structural damage in OA and examine current targets that are candidates for disease modification. The challenges to drug development and the obstacles to disease modification strategies will also be addressed.