Hormones and the Immune System

• CE credit for the presentation is provided by AKH Inc., Advancing Knowledge in Healthcare.
• AKH Inc. is jointly accredited by the ACCME, ACPE, and ANCC to provide continuing education for the healthcare team.
• AKH Inc., designates this live activity for a maximum of 24.0 AMA PRA Category 1 Credit(s).

Objectives:

• Hormones directly affect the immune system.
• Gender significantly contributes to shaping individual immune responses.
• Estrogens and progestins have profound effects on the immune system and can modulate vulnerability to autoimmune diseases.
• Androgens play a role in immune function in both men and women.
• The complex nature of DHEA-immune interactions makes the direct effects of DHEA difficult to interpret.
• Thyroid hormones affect immune function.
• Melatonin is an immune modulator.
• Insulin plays a role in the immune system.
• Immunosenescence is the age-associated decline of the immune system.
• Possible mechanisms underlie sex differences in vaccine-induced immunity.

Disclosure Statement

• AKH Inc. has a policy to ensure objectivity, balance, independence, and scientific rigor in continuing education activities.
• Pamela Smith, MD, MPH, MS, owner of Center For Precision Medicine, disclosed relationships with Biotics Research, Doctors Data, Genova Diagnostics, MDLifespan PCCA and ZRT Laboratory
• All relevant financial relationships listed have been mitigated.

What Makes Up The Immune System?

• Tissues work in harmony to form complex systems, including the immune system.
• The immune system defends the body from pathogens, toxins, and infectious agents.
• Innate and adaptive immunity are the two main classifications of the immune system and protect the body from disease or illness.

Components of the Innate Immune System

• The innate immune system activates within minutes to hours after a foreign agent invades the body.
• The innate immune system includes two lines of defense.
• The first line: skin (epidermis), gastric acid, and mucus membranes.
• The second line: chemicals and cells released in the blood after exposure to a pathogenic stimulus.
• These cells are active since birth and are ready to act as soon as a foreign body enters the system.
• Potency is limited.
• Immunity remains throughout the individual's life once activated against a specific type of antigen.
• Immunity is inherited.
• The response recognizes all types of pathogens (viruses, bacteria, fungi).
• The same response is produced every time a pathogen invades the body.
• The diversity among the response produced is very low.

Components of the Adaptive Immune System

• The adaptive immune system is responsible for complex reactions and activates after the innate response is fully implemented.
• The antigen in the body is identified and a cascade of reactions starts in the form of an antigen-antibody reaction to attack the antigen.
• The system generates memory cells of antigens, and a response will be started soon after the entry of the same pathogen.
• Cells remain in silent mode and become active only when the antigen is identified.
• Cells develop over time.
• The response appears after a week or two. Delayed response type of immunity.
• Potency and effectiveness levels are very high.
• Combat cells are greatly specialized and powerful.
• Span of the developed immunity can be lifelong or short.
• Presence of memory cells, which identifies specific cells on each exposure.
• Diversity of response is very high.

Immune System

• Both immune systems share the same overall function, protection.
• Innate response is produced initially for complete elimination of the pathogen and adaptive immunity is produced after.
• Cells of both systems coordinate equally to produce an effective and long-lasting response, safeguarding against harmful pathogens.

Cells of the Innate and Adaptive Immune Systems

• Cells of the innate and adaptive immune systems originate in the bone marrow.
• Hematopoietic stem cells then give rise to two cell lines: myeloid and lymphoid cells.
• Myeloid cells give rise to red blood cells, platelets, neutrophils, eosinophils, basophils, and monocytes and become dendritic cells and macrophages representing the innate immune system.
• Lymphoid cells give rise to natural killer cells, T-lymphocytes, and B-lymphocytes representing the adaptive immune system.
• T-lymphocytes give rise to helper cells, regulatory cells or suppressor T cells, and cytotoxic or killer T cells.
• B-lymphocytes give rise to plasma cells which then produce antibodies.

Lymphoid Cells

• The lymphoid cell line produces natural killer cells, B-lymphocytes, and T-lymphocytes.

Natural Killer Cells

• Lymphocytes of the innate immune system that control tumors and microbial infections by limiting their spread, thus limiting subsequent tissue damage.
• Activation is controlled by the balance between complementary and antagonistic pathways initiated upon interaction with potential target cells.
• NK cells express activating cell surface receptors that trigger cytolytic programs, cytokine, or chemokine secretion.
• Also regulatory cells that engage in reciprocal interactions with dendritic cells, macrophages, T-cells, and endothelial cells.
• Limits or exacerbates immune responses.
• NK cell deficiency can occur congenitally from defects in three different genes.

B-Lymphocytes

• White blood cells of the lymphocyte subtype that create humoral immunity, by secreting antibodies.
• B cells present antigens and secrete cytokines.
• Express B cell receptors (BCRs) on their cell membrane, unlike T cells and natural killer cells.
• BCRs allow B cells to bind to specific antigens to initiate an antibody response.
• Types of B lymphocytes: plasmablast, plasma cell, lymphoplasmacytoid cell, memory B cell, B-2 cell-FO B cells, MZ B cells, B-1 cell, and regulatory B (B reg) cells.

T-Lymphocytes

• White blood cells divided into three groups that are essential to the immune system,.
• Helper T cells (Th1 and Th2)
• Regulatory cells (suppressor T cells)
• Cytotoxic cells (killer T cells)

Helper Cells

• T helper cells (Th cells), also known as CD4+ cells, are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system.
• Helper T cells aid other cells in destroying harmful organisms and facilitate immune cell activity via T cell cytokines.
• These cells suppress or regulate immune responses and are essential in B cell antibody class switching, activation and growth of cytotoxic T cells, and maximizing bactericidal activity of phagocytes.
• Helper T cells influence a variety of immune cells and the T cell response generated can be very important to help the body eradicate an infection.
• Helper T cells must determine which cytokines benefit the host.
• Understanding how helper T cells respond to immune challenges is of major interest in immunology. Knowledge may aid in treating disease and increasing vaccination effectiveness.
• The cells come in two forms: Th1 and Th2.

Type 1/Th1

• Macrophage and CD8+ T cells are the main partner cell types.
• Cytokines produced: interferon-y, TNF-B, interleukin-2, and interleukin-10.
• Cellular immune system stimulation promotes maximized killing efficacy of macrophages, and proliferation of cytotoxic CD8+ T cells.
• Type 1 cytokine IFN-y increases the production of interleukin-12 by dendritic cells and macrophages, and via positive feedback, IL-12 stimulates the production of IFN-y in helper T cells (promoting the Th1 profile).
• IFN-gamma also inhibits the production of cytokines such as interleukin-4 (an important cytokine associated with the Type 2 response) to help preserve its own response.

Type 2/Th2

• B cell, eosinophil, and mast cells are the main partner cell types.
• Cytokines produced: interleukin-4, interleukin-5, interleukin-6, interleukin-9, interleukin-10, and interleukin-13.
• Humoral immune system stimulation leads to proliferation of B-cells, B-cell antibody class switching, and increased neutralizing antibody production (IgG, IgM, IgA, and IgE antibodies).
• Type 2 response promotes its own profile using two different cytokines: Interleukin-4 acts on helper T cells to promote the production of Th2 cytokines, while interleukin-10 (IL-10) inhibits a variety of cytokines.

Regulatory Cells

• Suppressor T cells (Treg) or (T8 or CD8+ cells) control the activity of other white blood cells so they do not destroy normal tissue.
• Maintain order in the immune system by enforcing negative regulation on immune cells.
• Tregs are classified into natural or adaptive Tregs.
• Natural Tregs are CD4+CD25+ T-cells that develop and migrate from the thymus to perform their major role in immune homeostasis.
• Adaptive Tregs are non-regulatory CD4+ T-cells which acquire CD25 (IL-2R alpha) expression outside of the thymus and are induced by inflammation and disease processes.
• The exact immunosuppressive mechanism of T regulatory cells remains elusive.

Cytotoxic Cells

• Killer T cells (a kind of CD8+ cell) recognize and destroy abnormal or infected cells.
• Cytotoxic CD8 T cells fulfill this host defense.
• CD8 T cells control protazoan infections.
• CD8 T cells must be both powerful and accurate to eliminate infected cells while sparing normal cells, which exactitude is critical in minimizing tissue damage while allowing the eradication of infected cells.

Humoral and Cell Mediated Immunity

• The adaptive immunity is further divided into humoral and cell-mediated immunity.
• Humoral and cell mediated immunities have the same origin, are two types of adaptive immunity, activate upon exposure to foreign antigens, defend against pathogens, and create immunological memory.
• The key difference: humoral immunity is the production of antibodies.
• Humoral immunity operates with B lymphocytes and their antibodies and mainly fights extracellular pathogens identified by antibodies.
• Cell mediated immunity does not involve antibodies, it provides immunity against intracellular pathogens identified by T cell receptors and certain cancers.

Cytokines

• Cytokines are a broad category of small proteins involved in cell signaling, that are involved in autocrine, paracrine, and endocrine signaling as agents of immune modulation.
• Cytokines are peptides and cannot cross the lipid bilayer of cells so they cannot enter the cytoplasm.
• Cytokines are produced by many types of cells (macrophages, B lymphocytes, T lymphocytes, mast cells, endothelial cells, fibroblasts, stromal cells).
• Cytokines are important in health and disease, specifically in infection, inflammation, trauma, sepsis, and cancer.
• Types of cytokines produced by the body: Interferons, Interleukins, Chemokines, Colony-stimulating factors, and Tumor necrosis factor.
• Adverse effects of cytokines have been linked to disease processes (schizophrenia, depression, cancer, and Alzheimer's).
• Oversecretion of cytokines can trigger a cytokine storm

Hormones Have a Direct Effect

• The immune system and its response are affected by endogenous and exogenous factors, modulators and challenges.
• More active immune response occurs in females relative to males, leading to increased autoimmune conditions and different responses to pathogens and viruses.
• Estrogen, progesterone and testosterone affect immune cells quantitatively and qualitatively.
• Studies show the impact of hormones on cytokine production by various effector cells, and the impact on immunoglobulin production by B lymphocytes, granulocytes and natural killer cell activity.
• Sex hormone receptors exist on the thymus and spleen.
• Immune cells synthesize, store, and secrete hormones identical to endocrine gland hormones.
• The POMC hormones (ACTH, endorphin), the thyroid system hormones (TRH, TSH, T3), growth hormone, prolactin, melatonin, histamine, serotonin, catecholamines, GnRH, LHRH, hCG, renin, vasoactive intestinal peptide (VIP), and angiotensin II are hormones synthesized, stored, and secreted by immune cells.

Estrogen

• Estrogen has 400 functions in a woman’s body (supporting the immune system, anti-inflammatory action).
• Estrogens play a central role in immune responses and immune-mediated diseases.
• Estrogen receptors on immune response cells include thymocytes, macrophages, and endothelial cells.
• Estrogen-induced immunomodulation, which has been studied since the 90s, remains an area of growing interest.
• Estrogens enhance the humoral immune response and play important roles in autoimmune rheumatic diseases.
• Promote cell proliferation, exert dose-dependent effects, and act through peripheral metabolites in autoimmune-related diseases.
• Peripheral metabolic conversion of androgen precursors to estrogen metabolites occurs in peripheral tissues.
• The synthesis of active estrogen metabolites at cells involved in the immune response characterizes a similar final immune reactivity in both males and females.
• Sex hormones are implicated, with estrogens as enhancers of humoral immunity and androgens/progesterone/glucocorticoids as immunosuppressors.
• Several conditions may change serum and/or conversion rate, including the menstrual cycle, pregnancy, postpartum, menopause, age, chronic stress, altered circadian rhythms, inflammatory cytokines, and hormonal replacements, resulting in altered androgen/estrogen ratios.
• The circadian rhythms of cortisol and melatonin are altered, partially involving sex hormones.
• Autoimmune diseases are more common in women.
• Androgens promote autoimmune diseases with type 1 cytokine profiles (rheumatoid arthritis); whereas estrogens promote autoimmune diseases with type 2 cytokine profiles (systemic lupus erythematosus).
• Type 1 autoimmune diseases improve with decreased type 1 cytokines (fasting) or when type 2 cytokines rise (pregnancy).
• Type 2 autoimmune diseases improve when type 2 cytokines diminish (post-partum) or type 1 responses are stimulated
• Exogenous estrogens have been avoided for women with SLE due to the idea that estrogens could activate the disease.
• HRT may be a small increased risk of mild/moderate flares in women with lupus but major flare risk does not appear to be increased.
• HRT was not associated with an increased risk of disease flare and may actually improve RA disease activity.
• Estrogen plays a role in the regulation of cardiovascular physiology and the immune system through multiple cell types including immune and vascular cells.
• Estrogen action is mediated via interaction with estrogen receptors (ERs), ERa and ERẞ, and the G-protein coupled receptor 30/G-protein estrogen receptor 1.
• G protein-coupled estrogen receptor 1 (GPER) binds to estradiol and is involved in some rapid effects that estradiol has on cells.
• Estrogen deficiency in menopause is linked to increased potential for an unresolved inflammatory status.
• Estrogen influences both innate and adaptive immune cells.
• Estrogens have been shown to regulate numbers/functions of neutrophils, which include chemotaxis, infiltration, superoxide anion production, myeloperoxidase, induction of chemokines, and cytokines.
• Also alters macrophage function by regulating chemotaxis, phagocytic activity, and induction of cytokines, iNOS, and nitric oxide.
• It can enhance the differentiation of immature dendritic cells into mature functional ones and regulate cytokines and chemokines.

Oral Contraceptives

• Substantial evidence exists linking combined oral contraceptives with a lower incidence of hyperthyroidism.
• Oral contraceptive increases multiple sclerosis, ulcerative colitis, Crohn's disease, SLE, and interstitial cystitis.
• Progesterone only oral contraceptive are linked to dermatitis and are associated with increases in arthropathies.
• Oral contraceptives influence the susceptibility to autoimmune diseases, risk for several autoimmune diseases.

Progesterone

• Progesterone suppresses the immune response to prevent miscarriage.
• It depresses cell mediated immunity, enhances suppressor cell activity, and inhibits mitogen induced lymphocyte proliferation.
• High progesterone levels are immune suppressive which may be why patients with rheumatoid arthritis do better during pregnancy.

Testosterone

• Androgens have an immune suppressive effect on a woman’s body which increases T-cell suppressor activity.
• Polycystic ovarian disease will affect lymphocytes, with decreased T8 in 64% and of natural killer activity (NK) in 60% of patients.
• Increased T4/T8 ratio in 55%, significant negative correlation between androstenedione and testosterone, significant positive correlation between the decreased T8 lymphocytes and NK cells.
• Higher innate and adaptive immune responses exist in adult females, which results in less risk of developing most infectious diseases.
• Adult females show a better ability to clear viral infection in women.
• Women are at an increased risk of developing autoimmune diseases (rheumatoid arthritis, multiple sclerosis, SLE, Sjögren's syndrome, and autoimmune liver diseases).
• Sex hormones affect disease pathogenesis, and estrogens have been extensively examined.
• Androgens can play an important pathogenetic role in autoimmune liver diseases.
• Testosterone, the predominant gonadal androgen in men, affects the immune system due to its anti-inflammatory effect.
• Low testosterone levels are associated with increased metabolic risk and systematic inflammation.
• Testosterone deficiency is associated with pro-inflammatory cytokines.
• Testosterone replacement reduces pro-inflammatory cytokines.
• Testosterone replacement reduces suppressed inflammation through increases in anti-inflammatory cytokines and decrease in pro-inflammatory cytokines.
• High testosterone levels in men may lead to poor immune response to the influenza vaccine and overdose.

DHEA

• Functions of DHEA: Decreases cholesterol/fatty deposits and prevents blood clots.

• Increases bone growth/lean body mass/brain function and promotes weight loss.

• Supports the immune system and increases a sense of well-being.

• Helps the body repair itself/maintain tissues and helps a person deal with stress.

• Decreases allergic reactions and sensitivity of insulin/elevates growth hormone and triglycerides.

• Replacement of DHEA increases feeling of wellness/quality of life and activates immune function.

• Also improves sleep and has a positive effect on memory and stops growth hormone and damaging effects of stress.

• Decreases joint soreness and sensitivity or insulin/elevation of growth hormone.

• DHEA is studied on its effects on immune function.

• Actions on androgen receptors/estrogen means DHEA is useful as a therapeutic.

• Actions are in levels of High Inflammation/altered adrenal production.

• Convoluted nature of DHEA-immune makes difficult effects to interpret/ needs considerate/intracrine.

• DHEA response to acute stress a factor in immune responses/depends on other hormones: Cortisol/DHEA-S.

• DHEA activated on daily basis- significantly activates immune function.

Cortisol

• Normal cortisol levels are needed to maintain the immune system.
• If cortisol levels are too high or too low, the immune system is compromised, not only in preventing infection, but also in its dysfunction involved in developing autoimmune disorders, malignancies, and other diseases.
• Cortisol is implicated in altered immune function: leads to exacerbated illnesses/psychological illnesses.
• Alters the release of antibodies, T cells.
• Shifts from cytokine expression, pro inflammatory cytokines, can activate the system.

Pregnenolone

• Shown to have beneficial effects in the brain, memory enhancements, reverse depression, modulating functions.
• Decreased levels in neuroinflammatory diseases, roles in protection/neuro-regeneration. Neuro steroid.
• Anti inflammatory in ubiquitin process- in innate system.
• Innate immune system recognizes pathogens through toll receptors.

Thyroid

• earliest signs of symptoms from the process can occur before lab studies may seem abnormal

• Many Signs and Symptoms associated with low thyroid: depression, weight gain, irregularities + more

• T3 drives proinflammatory and cytotoxic adaptive responses

• The immune system includes cells that protect against foreign antigens, such as cancer cells, toxins, etc

• The immune system protects against intruders, adaptive system against the antigens.

• The immune effects of T3+T4 immune cell subsets: neutrophils, natural killer, macrophages.

Melatonin

• Produced from the Pineal Gland, GI, tracts, & white blood cell to aide with sleep- Vitamin B6
• Melatonin Receptors all over for; intestines, fat, tissues, Liver. Functions: Acts as an antioxidant Blocks estrogen from binding to receptors Decreases cortisol levels to aide the stress response Stimulates the parathyroid Guards against Reflux Prevents against memory loss Lowers Inflammation Foods are; Tart Cherries, peanuts barley. It helps with the immune system and can be a potential therapeutic value for the aged. Side effects & Contraindications that it immune stimulates autoimmune- with to much serotonin levels can decline.

Insulin

• In a patient, it can lead with inflammation with the system, by overeating to lead to suppression, may need counter act what suppresses such as signaling

• Contributes to inflammatory Cascade.

• A mass amounts of weight/obese can affect one for immune.

• Diabetes also dysfunction with the immune- spread and invading the pathogens if one is affected by infections/and more susceptible

• An increase level of type 2- increase the infection/comorbidity factors.

• Females typically develop higher antibody responses/adverse reactions.

• Biological/Behavioral- Differences and contribute vaccine of outcome-hormones.

• Balance is a great aspect due to that and finding ways to decrease adverse reactions and the outcome of the immunization process for both sexes against infectious disease.