Allergy and Immunology: Cool cats and Hot topics Katherine Gundling, - PDF document

Allergy and Immunology: Cool cats and Hot topics Katherine Gundling, MD Professor Allergy and Immunology, UCSF December, 2015 No conflicts of interest

Topics The human female immune system Mepolizumab Sublingual immunotherapy Chronic urticaria/angioedema Dementia “Immune Dysregulation in Women”

Immune Dysregulation in Women The Magnificent Female Human Immune System Why do I say that? Our immune systems adapt amazingly to: Swings of multiple hormone levels The development of a half alien inside our wombs The simultaneous and somewhat opposite immunologic challenges of mother and fetus Providing immune protection to the infant via breast milk and mother’s microbiota Increased exposure to microbes via growing children Microbial assaults from other humans and the natural world, tumorogenic triggers from within and from the environment And sometimes we live more than 100 years!

Humans are born with a slight Th2 skewing – The immune system is trained toward an appropriately balanced state with environmental exposures: ‐ Microbes in the birth canal ‐ Barn animals ‐ Infections ‐ Wide variety of antigens The good news: Women have a lower burden of bacterial, viral and parasitic infections most evident during reproductive years Mycobacterium tuberculosis Adult males are most susceptible Malaria Adult males are most susceptible Viral infections Adult males are more susceptible to HIV, West Nile Virus, several hantaviruses

Estrogen can induce or repress the expression of key cell surface markers that are exploited by viruses; Sometimes this occurs only with certain genetic signatures The challenges: Women have more hypersensitivity Women have more autoimmune disease Pregnancy We used to think that pregnancy was a state of “low immunity,” that the immune system was somehow downregulated or turned off in order to allow implantation and growth of the fetus. In fact, pregnancy is a state of active , adaptable immunity , not passive “low” immunity

The immunologic state of pregnancy Dendritic cells Uterine NK cells ‐ regulate decidua stromal cell differentiation, helping to prepare for blastocyst implantation Increased frequency of FoxP3 ‐ expressing Treg cells in the blood of pregnant women (peaks second trimester)  Similar in mouse models, with pregnancy loss seen in Treg depleted states  Likely decreased levels of pro ‐ inflammatory cytokines IL ‐ 12 and TNF ‐ alpha The decidua and placenta are immunologically active and can affect the mother’s response to infection

Compared to non ‐ pregnant women, pregnant women are particularly susceptible to which organism? A. Haemophilus influenzae B. Listeria C. Pseudomonas D. Tuberculosis Answer: B The trade off for immunologic adjustment to the fetus is vulnerabilities of defense against some pathogens: Listeria monocytogenes Rubella Influenza Herpes simplex Toxoplasma gondii (poor outcomes for the fetus)

The trade off for immunologic adjustment to the fetus is vulnerabilities of defense against some pathogens: Listeria monocytogenes Rubella Influenza Herpes simplex Toxoplasma gondii (poor outcomes for the fetus) Pregnancy and Influenza During the 2009 H1N1 pandemic, pregnant women accounted for 5% of the deaths (and 1% of the population) Emerging evidence of a more vigorous immune response than seen in non ‐ pregnant women, with T cells and NK cells producing a (perhaps too) robust cytokine response Kay A, et al. Enhanced natural killer ‐ cell and T cell responses to influenza A virus during pregnancy. PNAS 14506 ‐ 14511; October, 2014

“How to BOOST YOUR IMMUNE SYSTEM during pregnancy..” “naturally….” “5 ways….” “20 ways….” “diet” “exercise” Summary The human female immune system is amazing and versatile! Pregnancy is a state of immunologic adjustment that requires balance between maintaining the fetus and protecting the mother. Influenza virus may be more deadly during pregnancy in part because of an elevated inflammatory response. Administer the influenza vaccine!

Mepolizumab has recently been approved to treat which condition? A. Eosinophilic esophagitis B. Hypereosinophilic syndrome (HES) C. Nasal polyposis/chronic sinusitis D. Severe asthma Answer: D Compared to men, women tend to have more hypersensitivity disorders

Asthma prevalence Prepubertal Boys have asthma about twice as often as girls of the same age Young adulthood By age 40 women are twice as likely to suffer asthma as men of the same age Post ‐ menopausal – Levels out slightly Asthma in women: More severe More hospitalizations Greater chance of death Observations:  Estrogen is associated with increased airway inflammation  Testosterone is associated with reduced airway activity  Sex specific differences in regulation and expression of genes associated with asthma

Hypotheses Genetic differences in lung mechanics Diagnostic and therapeutic bias Variable allergen exposure, and response to the allergens (women also have more allergic rhinitis, drug allergy and anaphylaxis) Is there a gender specific response to histamine? Mepolizumab “Anti ‐ IL ‐ 5”  IL ‐ 5 is the main cytokine responsible for maturation and differentiation of eosinophils  Part of the “T H 2” immune response Mepolizumab has just been approved for use in patients 12 years and older, who have refractory asthma of the eosinophilic phenotype. Administration is a once monthly injection in the office Pregnancy registry in progress Ortega H, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. NEJM 2014; 371:1198 ‐ 1207

Summary Mepolizumab is a humanized monoclonal antibody just approved for treatment of severe asthma, and is appropriate for the “High T H 2” phenotype. Allergic Rhinitis/Asthma/Conjunctivitis Inhaled Allergens Categories of Management options: 1. Maximal preventive measures 2. Treatment of symptoms 3. Retraining of the immune system

Sublingual Immunotherapy Approved for use in the US in 2014, for allergy symptoms caused by environmental exposure to pollens of rye grass family, and ragweed. New for 2015: Dust mite SLIT has received approval for use in Europe and Japan Unclear when it will be approved in the US S ub l ingual I mmuno t herapy SLIT ‐ tablets – Rapidly dissolving tablet held under the tongue until dissolved – Self ‐ administered, once daily SLIT ‐ drops (approved in Europe but not the US ) – Extract of allergen held under the tongue, then swallowed – Self ‐ administered, once daily

Mechanism of Action Changes to both humoral and cellular immunity Antigen uptake by mucosal dendritic cells Presentation to T cells in the draining lymph nodes Activation of T regulatory cells Upregulation of IL ‐ 10 Increasing levels of specific IgG4 Downregulation of mucosal mast cells/effector cells Blunting of seasonal increases of specific IgE Increased CD8+ T cells Advantages of SLIT Can be self ‐ administered at home (for the most part) Probably safer than SCIT Disadvantages of SLIT Limited kinds of antigens (allergens) May not work quite as well as SCIT Long ‐ term benefit of SCIT is better known

Adverse effects/contraindications of SLIT  >/= 5% experience itching/pain of the oropharynx  Cough  Risk of systemic reactions  Not for pts with severe, uncontrolled asthma  Prescribe epinephrine and train in appropriate use Approved for use in Europe in 2008 and authorized in 31 countries More than 20 million doses have been given to more than 110,000 pts. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Summary Sublingual immunotherapy is worth considering for some patients: 1. Limited specific allergic triggers 2. Asthma of concerning severity 3. Unable to devote the time to SCIT ?dust mite SLIT approval in the next year.

Urticaria Acute urticaria is frequently due to allergy Chronic urticaria (>6 weeks) is seldom due to allergy. Think “autoimmune” etiology Chronic urticaria is about twice as common in women as men It typically begins in the 3 rd to 5 th decades of life Mast cell Degranulation Image: Wikipedia

Mechanism of chronic urticaria: Not fully elucidated, but IgG antibodies probably trigger degranulation of mast cells and basophils by attaching to:  IgE  Fc epsilon RI (cell receptor)  Fc epsilon RII (cell receptor) Kapan, AP. Chronic urticaria: pathogenesis and treatment. J All Clin Immunol 2004; 114(3):465 ‐ 74 News Flash! Omalizumab (Xolair) ‐ anti IL ‐ 4, previously approved for for severe asthma, is now approved for use in chronic urticaria Significant improvement after just 1 ‐ 2 doses in 60 ‐ 70% of patients.

Clinical Pearl There is nothing magical about diphenhydramine (sedating, short acting) The vast majority of patients do fine with non ‐ sedating, long acting antihistamines, and the price has dropped significantly. Loratidine and cetirizine are Pregnancy category B, they last closer to 24 hours, and are much less sedating Fexofenadine, non ‐ sedating, is still category C Another news flash!