Immune Dysregulation in Women

Educational Objectives

The goal of this lecture is to improve the understanding of immune dysregulation. After hearing and assimilating this lecture, the clinician will be better able to:

1. Predict immune function based on age and sex.

2. Explain adaptations of the immune system that permit implantation and development of the fetus in the uterus.

Summary

Introduction: innate immune system — functions immediately upon injury or invasion by organisms; does not require specific antigenic responses, but rather uses patterns to detect whether problem bacteria, fungus, or other issue; innate system has minimal immunologic memory; natural killer (NK) cells have some memory; adaptive immune system — produces delayed, nuanced response based on signals received from innate immune system; memory key element of adaptive immunity

Time course: innate immune system works within 0 to 4 hr; early, induced phase (4-96 hr) features recognition of microbes and recruitment of inflammatory response; adaptive immune response (production of specific lymphocytes that produce antibodies) may take 2 wk; example — timeline illustrated by influenza vaccination; in vaccinated individual, immune system does not require 2 wk to respond; upon vaccination, innate immune system processes antigens and presents key molecules to T lymphocytes; T lymphocytes mature and instruct B lymphocytes to produce antibodies; upon subsequent exposure to influenza, immune system responds rapidly

Tolerance: some organs (eg, cornea and brain) can turn off immune system using immunologic tolerance; tolerance allows organism to differentiate between self and foreign cells and thereby avoid attacking self

Challenges: some viruses (eg, human immunodeficiency virus [HIV]) hide inside cells; cancers can grow unchecked if normal signals for inducing cell death become disabled; if body attacks self and patient loses tolerance to self, autoimmune disease results; if “off” signal for inflammatory response does not occur, patient may develop autoinflammatory disease; neutral visitors (eg, cat dander and dust mites) may generate Th2 inflammatory response and produce antibodies that cause mast cell degranulation, allergies, and asthma

Sex differences: differences in immune response between men and women evident throughout lifespan; genetic profile at conception helps define immunologic future

Fetal life: first immune cells detectable by 10 wk gestation; exposure during pregnancy affects immune system of child later in life; humans born with slight skewing toward Th2; Th2 manifested by production of antibodies (humoral immunity), with consequent predilection for atopic dermatitis, food allergy, allergic rhinitis, and asthma

Early environment: first 6 mo of life play key role in development of immunity; antigenic exposures of child living in urban environment differ from those of child on farm; children exposed to farm animals and their byproducts less likely to have allergies and asthma; X-linked diseases — affect boys; these include some primary immunodeficiencies; sudden infant death syndrome (SIDS) — more common in boys; often occurs when testosterone production initiated; testosterone may be associated with stronger inflammatory responses to infections

Asthma: hypersensitivity disease; sex predilection — boys have more asthma than girls, but sex predilection switches at puberty; by 40 yr of age, women twice as likely as men to have asthma; compared with men, women with asthma have more severe disease, more hospitalizations, and greater risk for death due to asthma; sex hormones — estrogen associated with increased inflammation of airway, whereas testosterone associated with reduced activity; other hypotheses — sex-specific differences now recognized in regulation and expression of genes associated with asthma; other hypotheses include differences in lung mechanics between sexes and greater contact with medical system in women (resulting in greater likelihood of diagnosis of asthma); women may spend more time in home and have greater exposure to dust mites, cat dander, and other allergens; more time in home may also be associated with higher likelihood of vitamin D deficiency (associated with infections, which may trigger asthma); gender-specific responses to histamines may exist

Pregnancy: immune tolerance allows child to develop in uterus; uterine NK cells and dendritic cells play key role in immunologic environment that permits implantation and development of fetus; in pregnant women, T regulatory cells dampen inflammatory responses; T regulatory cells in blood increase during pregnancy, peaking in second trimester; mice depleted of T regulatory cells have increased pregnancy losses; however, because of immunologic tolerance, mother vulnerable to infections such as rubella, listeriosis, influenza, herpes, and toxoplasmosis; decidua and placenta immunologically active; placenta influences maternal response to some organisms

Infections in adults: men more susceptible to tuberculosis, malaria, and some viruses (eg, HIV, West Nile virus, and some hantaviruses); reason undetermined; estrogen can induce or repress expression of cell surface markers exploited by viruses and might allow flexible response to these viruses

Vaccination: healthy women given half dose of influenza vaccine mount immune response equivalent to that of men given full dose; women have greater response to same dose; this may be related to robust Th2 humoral antibody response observed in women; however, undetermined whether greater response associated with greater protection; greater response might be associated with enhanced pathogenic immune activation against self; women respond to infection, vaccination, and trauma with increased production of antibodies (Th2-prominent immune response); men have increased cell-mediated response (production of interferon-γ, interleukin-2, and other cytokines)

Antibodies: naturally occurring autoantibodies clean cellular debris and repair damage; these antibodies measurable in individuals without previous exposure; autoantibodies more abundant in women than in men; number of different autoantibodies predicts risk for autoimmune disease and increases with age in both sexes; women account for 78% of patients with autoimmune diseases; inflammatory conditions predominant in men include pulmonary fibrosis, myocarditis, and idiopathic pulmonary fibrosis; in male mice, infection with coxsackievirus causes prolonged inflammatory response; however, female mice produce T regulatory cells that dampen this response and are therefore less likely to develop myocarditis

Readings

Ghosh M et al: The immune system in menopause: pros and cons of hormone therapy. J Steroid Biochem Mol Biol 2014 Jul;142:171-5; Giefing-Kröll C et al: How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell 2015 Jun;14(3):309-21; Martocchia A et al: Sex steroids in autoimmune diseases. Curr Top Med Chem 2011;11(13):1668-83; Muñoz-Cruz S et al: Non-reproductive effects of sex steroids: their immunoregulatory role. Curr Top Med Chem 2011;11(13):1714-27; Oertelt-Prigione S: The influence of sex and gender on the immune response. Autoimmun Rev 2012 May;11(6-7):A479-85; von Mutius E, Vercelli D: Farm living: effects on childhood asthma and allergy. Nat Rev Immunol 2010 Dec;10(12):861-8.

Disclosures

For this lecture, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Gundling was recorded at the Women’s Health Conference, held April 30 to May 2, 2015, in Santa Barbara, CA, and presented by the UC Davis Health System Office of Continuing Medical Education and Women’s Cardiovascular Medicine Program. For information about upcoming CME activities from the UC Davis Health System, please visit cme.ucdavis.edu. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this lecture.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OB631002

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.