Júlio Antônio Pereira Araújo

Sistema imunitário: Parte I. Fundamentos da imunidade inata com ênfase nos mecanismos moleculares e celulares da resposta inflamatória

The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the bodys homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the bodys homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.

Sistema imunitário - parte II: fundamentos da resposta imunológica mediada por linfócitos T e B

The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the bodys homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.

Células T regulatórias naturais (T REGS) em doenças reumáticas

The healthy immune system must keep the delicate balance between the capacity to respond to exogenous antigens and to keep the tolerance to endogenous antigens. In the absence of an adequate response to exogenous agents the individual is subjected to the deleterious effect of the invasion for pathogens. On the other hand, if the immune system responds in an unwary exacerbated way harmful inflammatory consequences may result. Well-established mechanisms of maintaining self-tolerance include clonal deletion and anergy. Despite the functional evidence in favor of the existence of suppressor T cells, for many years immunologists failed to identify the phenotypic characteristics and to confirm the existence of these lymphocytes. The recent demonstration of different phenotypes of cells, now designated regulatory T cells, reintroduced the paradigm of active regulation of auto-reactivity by particular subtypes of lymphocytes. This subject is of great interest in the contemporary literature. It has been shown that excess regulatory function may be associated with increased susceptibility to infectious and neoplastic diseases. On the other hand decreased regulatory function may cause autoimmunity. In fact, several experimental models of diverse autoimmune conditions have been developed by decreasing or abolishing regulatory T cells. Counterpart of this phenomenon has been sought for in several human autoimmune diseases. At this moment it seems that the most important subtype of regulatory cells are the natural regulatory T cells (TREGS), which represent about 5% of peripheral blood CD4 T lymphocytes. These cells are characterized by the constitutive expression of FOXP3, GITR, CTLA-4 and high levels of CD25. The present article reviews the basic knowledge on the TREGS and the several studies describing the status and function of these cells in autoimmune rheumatic diseased.

Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells

Objective: The identification of regulatory T cells (Treg cells) as CD4+CD25high cells may be upset by the increased frequency of activated effector T cells (Teff cells) in inflammatory diseases such as systemic lupus erythematosus (SLE). This study aimed to evaluate the frequency of T-cell subsets according to the expression of CD25 and CD127 in active (A-SLE) and inactive SLE (I-SLE). Methods: Peripheral blood mononuclear cells (PBMCs) from 26 A-SLE patients (SLE Disease Activity Index (SLEDAI) = 10.17 ± 3.7), 31 I-SLE patients (SLEDAI = 0), and 26 healthy controls (HC) were analysed by multicolour flow cytometry. Results: CD25high cell frequency was increased in A-SLE (5.2 ± 5.7%) compared to I-SLE (3.4 ± 3.4%) and HC (1.73 ± 0.8%) (p < 0.01). However, the percentage of FoxP3+ cells in the CD25high subset was decreased in A-SLE (24.6 ± 16.4%) compared to I-SLE (33.7 ± 16) and HC (45 ± 25.1%) (p < 0.01). This was partly due to the increased frequency of Teff cells (CD25highCD127+FoxP3Ø) in A-SLE (10.7 ± 7.3%) compared to I-SLE (8.5 ± 6.5) and HC (6.1 ± 1.8%) (p = 0.02). Hence the frequency of Treg cells (CD25+/highCD127low/ØFoxP3+) was equivalent in A-SLE (1.4 ± 0.8%), I-SLE (1.37 ± 1.0%), and HC (1.13 ± 0.59%) (p = 0.42). A-SLE presented an increased frequency of CD25+CD127+FoxP3+ and CD25ØFoxP3+CD127low/Ø T cells, which may represent intermediate phenotypes between Treg and Teff cells. Conclusions: The present study has provided data supporting normal Treg cell frequency in A-SLE and I-SLE as well as increased frequency of Teff cells in A-SLE. This scenario reflects a Treg/Teff ratio imbalance that may favour the inflammatory phenotype of the disease. In addition, the increased frequency of T cells with putative intermediate phenotypes may be compatible with a highly dynamic immune system in SLE.

Sistema imunitário: parte III. O delicado equilíbrio do sistema imunológico entre os pólos de tolerância e autoimunidade

The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the bodys homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.

Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus.

Regulatory T (TREG) cells play an important role in maintaining immune tolerance and avoiding autoimmunity. We analyzed the expression of membrane molecules in TREG and effector T cells in systemic lupus erythematosus (SLE). TREG and effector T cells were analyzed for the expression of CTLA-4, PD1, CD28, CD95, GITR, HLA-DR, OX40, CD40L, and CD45RO in 26 patients with active disease, 31 with inactive disease, and 26 healthy controls. TREG cells were defined as CD25+/highCD127Ø/lowFoxP3+, and effector T cells were defined as CD25+CD127+FoxP3Ø. The ratio of TREG to effector T cells expressing GITR, PD1, HLA-DR, OX40, CD40L, and CD45RO was determined in the three groups. The frequency of TREG cells was similar in patients with SLE and controls. However, SLE patients had a decreased frequency of CTLA-4+TREG and CD28+TREG cells and an increased frequency of CD40L+TREG cells. There was a decrease in the TREG/effector-T ratio for GITR+, HLA-DR+, OX40+, and CD45RO+ cells, and an increased ratio of TREG/effector-T CD40L+ cells in patients with SLE. In addition, CD40L+TREG cell frequency correlated with the SLE disease activity index (P=0.0163). In conclusion, our findings showed several abnormalities in the expression of functionally critical surface molecules in TREG and effector T cells in SLE that may be relevant to the pathogenesis of this disease.

Th17 cells and CD4+ multifunctional T cells in patients with systemic lupus erythematosus

INTRODUCTION/OBJECTIVE Recent evidence suggests that abnormalities involving Th17 lymphocytes are associated with the pathophysiology of systemic lupus erythematosus (SLE). In addition, multifunctional T cells (MFT), i.e., those producing multiple cytokines simultaneously, are present in the inflammatory milieu and may be implicated in the autoimmune process observed in SLE. In the present study, we aimed to characterize the functional status of CD4(+) T cells in SLE by simultaneously determining the concentration of IL-2, IFN-γ and IL-17 in lymphocyte cultures under exogenous and self-antigenic stimuli. PATIENTS AND METHODS Eighteen patients with active disease, 18 with inactive disease, and 14 healthy controls had functional status of CD4(+) T cells analyzed. RESULTS We found that SLE patients presented a decreased number of total CD4(+) cells, an increased number of activated T cells, and an increased frequency of Th17 cells compared to healthy controls (HC). MFT cells had increased frequency in SLE patients and there was an increased frequency of tri-functional MFT in patients with active SLE compared with those with inactive SLE. Interestingly, MTF cells produced larger amounts of IFNγ than mono-functional T cells in patients and controls. CONCLUSION Taken together these data indicate the participation of recently activated Th17 cells and MTF cells in the SLE pathophysiology.

Abnormal phenotypic distribution of regulatory and effector T cells in octogenarian and nonagenarian women

INTRODUCTION aging is associated with several immunologic changes. Regulatory (Treg) and effector T cells are involved in the pathogenesis of infectious, neoplastic, and autoimmune diseases. Little is known about the effects of aging on the frequency and function of these T cell subpopulations. METHODS peripheral blood mononuclear cells (PBMC) were obtained from 26 young (under 44 years old) and 18 elderly (above 80 years old) healthy women. T cell subpopulations were analyzed by flow cytometry. RESULTS elderly individuals had lower frequency of several activated effector T cell phenotypes as compared with young individuals: CD3+CD4+CD25+ (3.82±1.93 versus 9.53±4.49; p<0.0001); CD3+CD4+CD25+CD127+(2.39±1.19 versus 7.26±3.84; p<0.0001); CD3+CD4+CD25+ (0.41±0.22 versus 1.86±0.85, p<0.0001); and CD3+CD4+CD25highCD127+(0.06±0.038 versus 0.94±0.64, p<0.0001). Treg (CD3+CD4+CD25+CD127øFoxp3+) presented lower frequency in elderly individuals as compared to young adults (0.34±0.18 versus 0.76±0.48; p=0.0004) and its frequency was inversely correlated with age in the whole group (r=-0.439; p=0.013). The elderly group showed higher frequency of two undefined CD25øFoxp3+ phenotypes: CD3+CD4+CD25øFoxp3+(15.05±7.34 versus 1.65±1.71; p<0.0001) and CD3+CD4+CD25øCD127øFoxp3+(13.0±5.52 versus 3.51±2.87; p<0.0001). CONCLUSIONS the altered proportion of different T cell subsets herein documented in healthy elderly women may be relevant to the understanding of the immunologic behavior and disease susceptibility patterns observed in geriatric patients.