Stress, Immunity and the HPA axis

Transcription

1 Stress, Immunity and the HPA axis The goal of these lectures is to discuss basic physiology associated with the control of stress and immunity. This lecture together with the previous one (biological rhythms) are an introduction to the last part of the course. The sections for this lecture are: Stress and the HPA axis Stress an Immunity Chronic Stress Models Autoimmune Diseases 31 Life is a series of chemical reactions occurring in compartmentalized environments. The main purpose of life is to keep itself alive Physiology, the study of how life works, is based on the simultaneous occurrence of the following three concepts: levels of organization structure / function relationship homeostatic regulation Cortisol Stress & and the Stress the HPA Response Axis What is stress??? How many definitions of stress do you know??? How many different stress types do exist??? Is there a common denominator for stress??? Why we call the HPA axis, the stress axis??? Acute and chronic stress responses??? What does stress have to do with production??? 1

2 Cortisol Stress & and the Stress the HPA Response Axis When threat-related information reaches the brain two different response are generated: 1) The brain automatically engages THE AMIGDALA, an emergency fear center. This sent emergency information to other parts of the brain mediating the stress response (Epi, sweat, rapid heart beat, increased blood pressure). 2) The brain engages the THALAMUS first and then the CORTEX. The latter analyzes the information and decides whether or not a stress response is required. If the threat is not real or the response triggered by the amigdala is excessive, prefrontal cortex inhibits the amigdala. If the threat is real the cortex support it and the body stays on alert. Stress pushes the homeostatic envelope to a point from which the system might recover, or to the starting point of system pathologies The amygdala provokes a series of changes in the brain s chemicals that puts the entire body in a stress mode. The amigdala does not check for accuracy of the threat. Another part of the stress signal goes to the cortex, the thinking part, to figure out what is going on. Then the information goes to the prefrontal cortex, and from here the amygdale receives a very clear message to relax. (This is what supposed to happen in a normal stress response). Cortical assessment of incoming stress signals are compared to those in memory associated with the hypocampus. All rational cortical integration is conveyed to the prefrontal cortex to provide a breaking signal to the emotional outburst from the amygdala. For a normal stress response all circuitry has to be functional Stress pushes the homeostatic envelope to a point from which the system might recover, or to the starting point of system pathologies 2

3 Stress pushes the homeostatic envelope to a point from which the system might recover, or to the starting point of system pathologies 3

4 Stress pushes the homeostatic envelope to a point from which the system might recover, or to the starting point of system pathologies Insulin-induced hypoglycemic test 4

5 Regulation of ACTH Other effects Metabolic effects of glucocorticoids 5

6 6

7 (2) regulatory T-cell subsets, cytokines, chemokines, complements and antibodies neurotransmitters, hormones, peptides (within) (without) (1) The immune system is controlled from within and from without as suggested by Medawer 1973 adaptive immunity takes 4 to 7 days to occur but is specific cells of the immune system innate immunity operates within hours but is nonspecific Multiple immune cells and their secretions regulate the immune response from within 7

8 Hormonal controllers of the immune system (thymus & bone marrow) (lymph nodes) Multiple hormones and neurotransmitters regulate the immune response from without (within) regulatory T-cell subsets, cytokines, chemokines, complements and antibodies neurotransmitters, hormones, peptides (without) acute vs chronic stress The immune system is controlled from within and from without as suggested by Medawer

9 some hormones and neurotransmitters in the immune tissue and immune modulators in brain found in the immune system found in the brain CRH, AVP, OT, GnRH, LH, ACTH, POMC, END, ENK, TSH, PRL, SS, GH, Nepi, SP IL1, IL6, TNFa, IL3, IFNg, TGF and their receptors The brain and immune system talking to each other is essential for maintaining homeostasis adaptive immunity takes 4 to 7 days to occur but is specific cells of the immune system innate immunity operates within hours but is nonspecific Multiple immune cells and their secretions regulate the immune response from within 9

10 Pro-inflamatory response Th1 / Th2 Anti-inflamatory response Multiple immune cells and their secretions regulate the immune response from within Pro-inflamatory response Th1 / Th2 Anti-inflamatory response The immune system is controlled from within and from without as suggested by Medawer

11 Stressors S E An example of circles, intersecting circels, intersecting acute vs chronic stress The neuroendocrine - immune connection has driven a reversal of reductionist approaches The corticosterone response is not generated against the challenge per se but, rather, is an attempt to regulate the response that is generated to the challenge (disease susceptibility?) acute vs chronic stress 11

12 The neuroendocrine - immune connection has driven a reversal of reductionist approaches IL-1 brain ventricle injection acute vs chronic stress Involvement of the PVN is a characteristic of the homeostatic response to stressors such as the hypoglicemic and other tests Chronic Stress Models A chronic stress model there is good correlation between the decrease in CRH-mRNA levels in the PVN and the increase in severity of inflamation low CRH and high AVP Adjuvant-induced arthritis model: hybridization with a probe complementary to CRH in PVN 12

13 Chronic Stress Models there is a decrease in CRHmRNA levels in the PVN that occurs despite activation of the HPA axis. With recovery, levels return to those seen in controls and at the preclinical stage. A chronic stress model low CRH and high AVP Allergic encephalomyelits model: hybridization with a probe complementary to CRH in PVN Autoimmune Diseases Diabetes type 1, a chronic stress model?? 13

14 Autoimmune Diseases Diabetes type 1, a chronic stress model?? Autoimmune Diseases Diabetes type 1, a chronic stress model?? 14

15 GAD, glutamic acid decarboxylase IA-2, islet antigen 2 Diabetes Mellitus type 1 Autoimmune Diseases 15