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IMMUNOLOGY SIMPLIFIED Autoimmune diseases Barb Bancroft, RN, MSN, PNP www.barbbancroft.com [email protected] Immunology… • Definition: The study of the physiologic mechanisms that allow the body to recognize pathogens and foreign proteins as self vs. non-self and to neutralize or eliminate those unfamiliar pathogens and proteins. • 3 General Principles… Recognition of SELF vs. Non-SELF MHC (major histocompatibility complex) • A small section on chromosome 6 containing a group of genes that produce molecules that mark a cell as “self”—called self antigens • Histocompatibility testing, or tissue typing, involves matching these self-antigens • Because tissue typing is usually performed on White Blood Cells (WBCs), or leukocytes, these selfantigens are called Human Leukocyte Antigens or HLA Human Leukocyte Antigens… • They were first studied on our WBCs by renal transplant surgeons in the 1960s • All tissues have HLA on them except red blood cells that have ABO antigens for blood typing • Of course, the HLA antigens weren’t put on tissues solely for the convenience of renal transplant surgeons… General principles—recognition of self vs. non-self • Human Leukocyte Antigens (HLA) are essential for immune system recognition of pathogens and to mount an immune response to those pathogens • Class I antigens—found on all body cells (except RBCs again) have HLA-A, HLA-B, HLA-C— known as Class I antigens • Class II antigens– known as HLADP, HLA-DQ, HLA-DR Class II antigens • Class II antigens are the immune response antigens and are located cells that play roles in immune recognition and response • Monocytes (circulate in blood) and “change”, their name to macrophages (in tissues—APCs*), dendritic cells aka Langerhan’s cells (in skin and mucosa just beneath the epithelial cells—APCs*), Langerhan’s cells, B lymphocytes (effector cells of the immune system) , activated T lymphocytes (effector cells of the immune system) • *Antigen Presenting Cells—process the “foreign” substance to present to the immune system Antigen presenting cell with a Class II HLA-DR group Class II --DR Macrophage Or B lymphocyte Or T lymphocyte Class II HLA antigens • These antigens are essential for immune function and survival • They determine which foreign antigens an individual responds to as well as the strength and type of response • These are also “secreted” in body fluids in lower forms of animals (including us)— help select a mate based on “strength” of the immune system to guarantee survival of the species—how do lower forms of animals meet? This is known as clonal selectivity • “Hello, Shirley…I’m Duke...yeah, and I’m George, back here behind Duke...” • Sniff, sniff, sniff, sniff, sniff… • Dogs stick their nose where the “sun don’t shine” and say… “You’re the one for me…” Whoa…just checkin’ Why don’t we stick our nose where the sun don’t shine? We have a “mother”—your frontal lobe… • “Don’t even think about it…” • CN 0 –The nervus terminalis— runs in parallel with cranial nerve 1 (the olfactory nerve) HLA and autoimmune diseases • Most autoimmune diseases are associated with specific HLAantigens—in other words, an individual will inherit specific HLAantigens that “predispose” that individual to an autoimmune disease • Some of these include: • Rheumatoid Arthritis (HLA-DR1, HLADR4) • Multiple sclerosis (HLA-A8, B8, DR3— 10x greater risk) • Ankylosing spondylitis (HLA-B27) • Celiac Disease (DQ2, DQ8) HLAs and autoimmune disease • For example…Type 1A diabetes—HLA-DR3 (5% risk), HLA-DR4 (6% risk), both? (20% risk), and DQB1—more prevalent in Scandinavians (Finland)… Blonde-hair, blue-eyed with… Polyuria (excessive urination), polydipsia (excessive drinking), polyphagia (excessive eating), weight loss, fatigue Historical highlights • Over a 100 years ago bacteriologist Paul Ehrlich coined the term “horror autotoxicus”—a term used to describe an immune system attack against a person’s own tissues. He thought such “autoimmunity”—another term he coined—was biologically possible yet somehow kept in check • Nobody believed him…fast forward-- Over 80 autoimmune diseases involving approximately 50 million Americans—to name a few… • Rheumatic—rheumatoid arthritis, psoriatic arthritis • Neurologic—multiple sclerosis, myasthenia gravis • Vascular—Kawasaki disease in kids, Henoch-Schonlein purpura in kids, ITP in kids (immune thrombocytopenic purpura)* giant cell arteritis (aka temporal arteritis) in adults over 50 • Endocrine—Hashimoto’s thyroiditis, Grave’s disease, Addison’s disease, vitiligo • Dermatologic—vitiligo, dermatomyositis, alopecia areata, psoriasis • Gynecologic—endometriosis • ITP in adults – lupus or HIV or HCV Over 80 autoimmune diseases 50 million Americans • GI—Crohn disease, ulcerative colitis, celiac disease • Hematologic—ITP, AIHA (autoimmune hemolytic anemia), pernicious anemia • Multi-system—systemic lupus erythematosus, MCTD (mixed connective tissue disease, polymyositis, systemic sclerosis (scleroderma) Where there’s smoke, there’s fire… • • • • • • Familial clustering (SLE, AIHA, Hashimoto’s thyroiditis) Individual with more than one Hashimoto’s Thyroiditis + Type 1 DM + celiac Rheumatoid Arthritis + Sjögren’s—30-50% of patients with RA have Sjögren’s, 8-30% of Systemic Lupus Erythematosus patients have systemic sclerosis Endometriosis –7x more likely to have Hashimoto’s; higher risk for MS, RA, lupus, SS, Chronic Fatigue Syndrome (100x), Fibromyalgia (2x) (Human Reproduction 2002) Raynaud’s phenomenon • 1862—French MD Maurice Raynaud 1st described this phenomenon that now bears his name as an exaggerated vasospastic response to cold temperatures resulting in transient digital ischemia • 20% of patients with Raynaud’s will ultimately have a concomitant disease. Causes include connective tissue diseases, such as SLE, dermatomyositis, Sjögren’s syndrome, RA, scleroderma, hypothyroidism • Calcium channel blockers such as nifedipine decrease the frequency of vasospastic events by 66% • Wigley FM. Clinical Practice. Raynaud’s phenomenon. N Engl J Med 2002; 347:1001-1008. Autoimmune diseases are tough to diagnose • Takes an average of five physician visits over an average of 3.5 years to finally be diagnosed properly (American Autoimmune Related Diseases Association, March 2016) • WHY? Lots of reasons, but the symptoms range widely and can overlap with other more benign illnesses • One symptom that is uniform throughout—profound fatigue; described as “debilitating” fatigue, “impacts every aspect” of their lives • HAVE A HIGH INDEX OF SUSCPICION if you are a PCP out there!!! The “spectrum” of autoimmune disease • Autoimmune disorders form a spectrum on one end of which are conditions in which autoantibodies are directed against a single organ or tissue, therefore resulting in local tissue damage—examples: Hashimoto’s thyroiditis, Myasthenia Gravis, Multiple Sclerosis • On the other end the autoimmune disease can damage multiple tissues—in other words, it is more systemic (systemic lupus erythematosus) • And of course, you can something “in-between” Hashimoto’s thyroiditis • Anti-microsomal antibodies • Anti-thyroglobulin antibodies Multiple sclerosis • Antibodies against myelin basic protein in the central nervous system • Optic nerve—changes in vision • Corticospinal tract--spasticity • Cerebellum—balance and equilibrium • Spinothalamic tract—pain Myasthenia Gravis (MG) • Meaning: “grave muscle weakness” (Latin & Greek) • Anti-acetylcholine receptor antibodies on skeletal muscle receptors • As many as 80% of the AcH receptors can be blocked or destroyed by the antibodies produced against it As an FYI: MG vs. MG • Myasthenia Gravis (MG as we know it) is not the only medical condition that is referred to as MG. • a STI (Sexually Transmitted Infection) caused by Mycoplasma genitalium is also sometimes abbreviated as MG. • Myasthenia Gravis has nothing to do with Mycoplasma genitalium. • Do not be confused if you run across an article about MG being sexually transmitted. • Myasthenia gravis is not transmitted from one person to another by intimate contact or any form of contact. On the other end of the autoimmune spectrum-- systemic lupus erythematosus, SLE or “lupus” • “LUPUS ERYTHEMATOSUS”—red wolf • Auto-antibodies directed DNA components, platelets, RBCs, and protein-phospholipid complexes results in widespread lesions throughout the body • Affects many systems—skin, musculoskeletal, renal, neuropsychiatric, hematologic, renal, cardiovascular, pulmonary and reproductive • 2x greater in black women than white women1/250 African American women aged 18-65 In between the single tissue attack vs. the multisystem attack you have… • Goodpasture’s syndrome, in which antibodies to basement membranes of the lung and the basement membranes of the kidney • The autoimmune response attacks the lungs and the kidneys Gender bias in most (but not all) autoimmune diseases • OVERALL: 75-80% involve women • Females mount more powerful immune responses than males, but the flip side of this enhanced protection against infections is a greater risk for autoimmune disorders. • May have something to do with the GI microbiome and hormonal influences • Animals raised without a gut microbiome show no gender differences in autoimmunity • Eunuchs (castrated males) have the same risk of autoimmunity that females do • Testosterone @ puberty changes microbiome to protect male • Yurkovetsky et al.: "Gender bias in autoimmunity is influenced by microbiota.” Cell Press, August 22, 2013 Direct hormonal influences on the immune system – gender biaS • Estrogen decreases regulatory T cells; Regulatory T cells normally suppress the response to self; loss of self tolerance more common in women • Estrogen increases the expression of gamma interferon, a cytokine that increases HLA antigen expression; this increased expression of HLA antigens on tissues may make the tissue appear foreign Autoimmune disease—female bias • RA (7:1); Sjögren’s (10:1); SLE (10:1) • Hashimoto’s thyroiditis (studies vary widely from 8:1 to 25:1 to 50:1) • MG—2:1 female to male, but with an interesting bimodal distribution--2nd and 3rd decades higher incidence in women, 6th and 7th decades, higher incidence in men • MS—3:1 Autoimmune diseases • It’s NOT just the genes…people can have the genes that predispose to various autoimmune diseases, but environmental (exogenous or endogenous) triggers play a role in “turning on” the genes • Some examples include: Triggers for genetically-predisposed individuals • The lack of vitamin D for certain autoimmune diseases (T1A DM? MS? Crohn’s disease?) • Norovirus and Crohn’s disease? • Endogenous triggers? Endogenous enterobacteria for Crohn’s disease and ulcerative colitis? • Exogenous triggers? Gluten in the diet? Celiac disease • Viruses/ protein in cow’s milk for T1A DM? • Multiple environmental factors Speaking of Vitamin D • Using new technology that recognizes the vitamin D receptor, researchers found 2,776 vitamin D binding sites along the human genome where vitamin D binds to the DNA, affecting the way it works. • They also found 229 specific genes that worked differently in response to vitamin D, AND, they found clusters of vitamin D receptors in areas of the genome responsible for various autoimmune disorders and cancers. (Ramagopaian SV et a. A ChiP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution Gennome Res. 2010;20:1352-60) • Vitamin D is also used to prevent Type 1 diabetes in Finland, and to treat patients with MS and Crohn disease How do endogenous and exogenous proteins trigger autoimmunity? • The principle of molecular mimicry • The “foreign” antigen appears similar to an antigen on endogenous/normal tissue • The immune response recognizes and attacks the foreign antigen, but “cross reacts” with the “self-antigen” due to similarities in the antigens between “self” and “non-self” • Two examples come to mind immediately • Campylobacter jejuni and Guillain-Barré syndrome • Group A beta hemolytic strep and rheumatic heart disease, acute post-streptococcal glomerulonephritis and PANDAS Campylobacter jejuni and Guillain-Barré syndrome • A protein (epitope) on C. jejuni is similar to a protein on peripheral nervous system myelin—immune system recognizes BOTH as foreign • Although C. jejuni infections are a common trigger of GBS (probably preceding ~40% of GBS cases), the risk of developing GBS after C. jejuni infection is actually quite small (<1 case of GBS per 1000 C. jejuni infections) • Symptoms occur 3-5 weeks after consuming the undercooked chicken • White meat—170° F • Dark meat and the whole chicken -- 180° F It’s not just C. jejuni-Other infectious causes of GBS • ZIKA virus • Cytomegalovirus • Mycoplasma pneumoniae • Epstein-Barr virus • Varicella Zoster virus Another digression…Guillain-Barré and the flu vaccine • Swine flu – 1976; 1 additional case per 100,000 vaccines • 3000-6000 cases in US/year regardless of whether or not the patient received a flu vaccine • Meningococcal vaccine (Menactra) is quadrivalent for a reason—even tho’ there are 6 serogroups of Neisseria meningitidis (A, B, C, X, Y, W135)—the vaccine leaves out type B due to antigenic mimicry with human polysaccharide in peripheral nervous tissue • NEW group B vaccines—Bexsero (given at ages 11 and 16)—doesn’t cross-react with peripheral myelin (Trumenba approved for ages 1025) Another example of molecular mimicry and “cross reaction” • the group A beta hemolytic strep antigen (epitope) cross reacts with cardiac glycoproteins (myosin-like) • acute rheumatic heart disease usually occurs 2 to 3 weeks after strep throat—murmur of mitral regurgitation, joint pain, rash Rheumatic heart disease—cross reaction with heart valves, joints, skin • • • • Mitral and/or aortic valve vegetations Endocarditis, myocarditis, pericarditis #1 cause of valve replacement prior to the age of 60 M strains (1,3,5,6,12,18,24 strep pharyngitis) of GABHS cross react with myosin proteins on heart • Genetic susceptibility Acute post-streptococcal glomerulonephritis is another example of molecular mimicry • M49 is associated with acute post-streptococcal glomerulonephritis in genetically susceptible individuals GABHS—possible cross reaction with basal ganglia and limbic system • PANDAS—Pediatric Autoimmune Neuropsychiatric disorders associated with Strep • Tic syndromes; OCD • Sydenham’s chorea (St. Vitus Dance)—Dr. Thomas Sydenham in 17th century 2nd general principle—selectivity and specificity • The immune system is highly selective and specific for each pathogen • 1 pathogen=1 response • “monoclonal” For example… • • • • How many types of strep are there? Over 200 (Group A thru O + hemolytic properties—alpha, beta, gamma)—Just because you have had 1 strep throat doesn’t mean you’re “immune” to all strep infections--BUMMER GABHS (Group A beta hemolytic strep— Group B strep • • One type of pathogen=one response to that pathogen Known as MONOclonal “Mono”clonal also applies to a class of drugs—monoclonal antibodies (MABs) • Monoclonal antibodies have been produced for specific types of cancer; for autoimmune diseases; to reduce allergic symptoms; to block viruses; to decrease new vessel formation (anti-angiogenesis); and more… • Infliximab (Remicade) for example • Adalimumab (Humira) • Rituximab (Rituxan) • “li” for immune system; “tu” for tumor • “u” human; “xi” murine or murine/human (chimeric) Monoclonal antibodies—immune system • Infliximab (Remicade)—targeted against the overproduction of the inflammatory product known as tumor necrosis factor-alpha (TNF-α), the culprit in Crohn’s disease, Ulcerative colitis, Rheumatoid Arthritis, psoriatic arthritis, ankylosing spondylitis • Adalimumab (Humira), certolizumab pegol (Cimzia) Monoclonal antibodies • Rituximab (Rituxan)—monoclonal antibody to CD20 (marker on B lymphocytes)—Non-Hodgkin’s lymphoma, Myasthenia Gravis, and other autoimmune diseases • Omalizumab (Xolair)—mab to IgE to decrease allergic symptoms caused by histamine; block the release of histamine from mast cells • Belimumab (Benlysta)—Systemic Lupus Erythematosus (targets B lymphocyte activating factor) rd 3 general principle—memory • Once having met a pathogen, the immune system “never “ forgets it. • If you are re-challenged with the same pathogen the memory response will recognize it immediately-- and destroy it or neutralize it. There are always exceptions to every rule and principle… • One big exception: the aging immune system tends NOT to remember as well There are always exceptions to every rule… • Patients on immunosuppressive drugs have immune systems that are suppressed and “can’t remember”… SO, with such a fabulous memory we should never get the same disease twice! And that’s true, MOST of the time… HERPES is an exception!! The immune system recognizes herpes, responds to herpes, but can’t KILL it… The HERPES “Family” • HSV-type 1 and HSV-type 2 –herpes “cold sores” and herpes genitalia • VZV (varicella vaccine)—shingles, Herpes zoster • Epstein-Barr virus—mono, B-cell lymphoma • CMV—cytomegalovirus – gastrointeritis, pneumonitis, retinitis, ? Glioblastoma • HHV-6, HHV-7--rubeola • KSHV (HHV-8)—Kaposi’s sarcoma (cancer of the endothelial cells of the blood vessels) Herpes simplex virus--type 1 and 2 • Above and below the belt Varicella zoster virus—(chickenpox/shingles) • VZV—varicella zoster virus • Primary infection is chickenpox—crawls up the sensory nerve and lives in dorsal root of the brainstem and spinal cord • If your immune system is “competent” , the virus remains dormant • Immunosuppression increases the risk that the virus will express itself as the secondary manifestation of shingles or herpes zoster, aka, HELL’S FIRE Immunocompromised? Shingles is the secondary manifestation • Hematologic malignancy; rate of HZ is 5-25% • Lupus—3.2-21% • HIV/AIDS increases risk by 12-17 fold (T cell deficiency)—multi-dermatomal shingles • Depression and significant stress within past 6 months increases risk • The elderly Shingles is more common in the aging population • With aging population, the absolute # of herpes zoster cases is increasing dramatically; Why? • Because the type of immunity that keeps latent herpes in a “latent” state wanes with aging—this type of immunity is called cellmediated immunity (CMI); killer T cells are responsible for CMI and their action decreases with age FYI: Percent of individuals with shingles, by age • • • • • • • • • • 10—0.5% 20—1.3% 30—2.7% 40—4.8% 50—7.5% 60—11.9% 70—19.7% 80—31.8% 90—46.1% Donahue JG, et al. Archives of Internal Medicine, 1995. Location, Location, Location… • • • • • • • 4% sacral 11% cervical 13% cranial (ophthalmic) 13% lumbar 56% thoracic 3% other Ophthalmic complications 10-25% (keratitis, iritis, retinitis, optic neuritis with vision loss and blindness) • AIRBONE precautions for disseminated herpes zoster Treatment of Herpes Zoster • Acyclovir (Zovirax)—800 mg/day po 5x/day x 7-10 days; significant reduction in severity, duration and relative risk of postherpetic neuralgia • Famciclovir (Famvir)—500 mg po 3x/day x 7 days—as effective as Zovirax in reducing acute pain and preventing PHN • Valacyclovir HCl (Valtrex)—1000 mg/po 3x/d x 7 days provides an improved benefit over acyclovir in reducing the severity and duration of PHN in patients over 50 • Start treatment within 48 to 72 hours of rash onset; nerve block? • What about Prednisone? Vaccine to prevent shingles—Zostavax at age 50 • Vaccine approval May 2006 • PHN – vaccine reduces incidence of HZ by 51% and decreases incidence of PHN by 66%; decreases morbidity by 61% • Patients older than 50 have a 14.7-fold higher incidence of chronic pain 30 days after the onset of rash than patients under age 50 • NEW VACCINE on the horizon—much better efficacy The Epstein-Barr* virus (EBV) is a member of the Herpes “family” • • • • • *(Dr. Tony Epstein and his lovely assistant, Ms. Yvonne Barr) Lives in your B lymphocytes forever Burkitt’s lymphoma MONO B-cell Lymphoma (the boy in the bubble—David Vetter)—common lymphoma in AIDS patients—as their immune systems decline, the EBV reactivates in their lymph nodes and triggers uncontrolled growth-lymphoma • Nasopharyngeal carcinoma • ? MS Cytomegalovirus … • CMV (cytomegalovius)—gastroenteritis, retinitis, pneumonitis— wreaks havoc in immuno-compromised patients • Crosses the placenta and can cause cytomegalic inclusion disease in developing babies Cytomegalovirus • Glioblastomas harbor a strain of CMV not found in surrounding neuronal tissue • Average survival time between dx and death is 12-15 months; however, Duke University studied dendritic cell immunotherapy—the use of the patient’s own dendritic cells with a CMV-targeted toxin attached and reinfused into the patient (a dendritic-cell vaccine)—purpose is to signal the immune system to mount an attack • Giving a tetanus shot WITH the dendritic cell vaccine increased survival time by 50% in most patients—however, one lived 4.8 years, another 5.9 years, and one is still alive 8.8 years post therapy. • (Baatich K. March 11, 2015 Nature) Two other well-known pathogens (and one other not-so-well known)the immune system recognizes • But can’t destroy… LEARN TO PROFILE! • TB—immigrants—China, Russia, Romania, India, Mexico, Philippines • Hepatitis C—Baby Boomers!! (1945-1965) JC Virus (especially important in the immunocompromised patient) • JC virus (John Cunningham virus)—drugs that severely compromise patients (specifically drugs for MS, Crohn’s disease) can cause a reactivation of this virus and lead to a devastating neurologic disease called PML (Progressive Multifocal Leukodystrophy)—(natalizumab/Tysabri, (dimethyl fumarate)Tecfidera, verdolizumab/Entyvio) • Can test for JCV antibodies—if + you have the JCV as a latent virus; If the test for JC virus is found to be negative (often referred to as JCV negative) the risk of PML is very small (less than 1 in 1,000). IF the test is positive, the risk of PML is 12x higher • Plavina T, et al.Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy.Annals of Neurology 2014;76(6):802-12. So let’s go back to the MEMORY of the immune system…how do you acquire memory? • You either suffer the infection… • OR YOU… VACCINATE!! • VACCINATE, VACCINATE, VACCINATE How does the immune system develop memory? • It meets a pathogen, responds to it, and that response can be measured as a memory response • Antibodies are made to pathogens and we measure those as “titers”— What do antibody titers tell us? • Antibody titers can give us lots of information: 1) tell us if you have EVER been exposed to a specific pathogen, ie. memory—varicella titers, CMV titers 2) tell us if you have responded to a pathogen/vaccine and how strong that response was/or currently is—levels of titers 3) antibodies can tell you something about the disease stage (IgM vs. IgG—acute phase vs. convalescent phase or early vs. “memory”)—more later 4) antibodies to “self”—autoimmune antibodies to diagnose autoimmune disease 5) these titers tend to wane as we age—we just can’t remember like we used to… Autoantibodies—measuring antibodies to “self” • Hashimoto’s antibodies to components of the thyroid gland—antimicrosomal antibodies, anti-thyroglobulin antibodies • Type 1A diabetes—antibodies to components of beta cells of the pancreas; anti-glutamic acid decarboxylase antibodies, anti-islet cell antibodies • Primary Biliary Cholangitis (old name, primary biliary cirrhosis)—antimitochondrial antibodies • Systemic Lupus Erythematosus--auto-antibodies are directed at DNA (anti-Nuclear antibodies/ANAs, platelets, RBCs, and proteinphospholipid complexes Let’s get back to vaccines for a moment…historical highlights • Historical highlights • Chinese vaccines—10th century B.C. – “sowing the pox”—injecting pus from the smallpox pustules into a cut on the hand of a healthy person; “snorting” the pox was another way of inoculating against small pox Historical Highlights… • 1796--Edward Jenner and the milkmaid--cowpox (“vacca” is the Latin word for cow) offering protection against smallpox; “vaccinia”=cowpox • His prediction? 1976…last case of smallpox in Somalia • Small pox • Great pox • Chicken pox World Health Organization and “herd” immunity • Vaccinating 70% of the world’s population against smallpox developed “herd” immunity • Why were we able to totally eradicate smallpox from the face of the earth? WHO and “Herd” immunity • “herd” immunity is defined as the population immunity level needed to interrupt transmission • In other words, if you vaccinate enough people in a community the virus/pathogen can’t spread • The herd-immunity threshold for measles is 92-94% to prevent sustained spread of the virus; • Currently only 91% of kids in the U.S. are vaccinated against the measles • The average person with measles is capable of infecting 12 to 18 other people if all his or her contacts are susceptible. Herd Immunity • Herd immunity for polio is 80-86%--if you have polio you are capable of infecting 5-7 other people…lower herd immunity because it is less infectious than measles Herd immunity • Mississippi and West Virginia--99.5% of kids are vaccinated (because there are no legitimate reasons to OPT out, except for age and an immunocompromised status); • California in spring and summer 2014? Less than 92%-(parents opting out for “religious” reasons, personal reasons, “the risk of autism”, blah, blah, blah…92% of the 2015 January cases are traced back to the Southern California outbreak, where the most fervent antivaxxers live* • Index case for the 2014 measles epidemic was a child from the Philippines with an acute case of measles at Disneyland in Anaheim, California) The lack of “herd” immunity • Schools in some of Los Angeles wealthiest neighborhoods were notorious for having similar vaccination rates to developing countries like Chad and South Sudan. • At the Kabbalah Children’s Academy preschool in Beverly Hills, 57% of parents have filed a personal belief exemption from vaccinations as have 68% at the Waldorf Early Childhood Center in Santa Monica. • In other words, more parents had BOTOX shots than their kids had vaccines in LA • Hollywood Reporter The WEEK 2/13/15 The Good News…politicians finally wised up… • California Government just passed a law that parents cannot “opt” out for religious/personal belief reasons…if they do, they have to home school or have private tutors • Joins WVA and Mississippi with the most strict vaccination laws Anti-vaxxers have a new “mantra”—too many antigens presented at one time with vaccines • The smallpox vaccine alone contained 200 different smallpox specific antigens—had the potential to overwhelm the immune system • All vaccines today contain approximately 150 antigens combined • Kids are exposed to approximately 6,000 foreign antigens every day… Vaccines… • Prevention of childhood diseases…(kid receive over 20 vaccines by the age of 2 if they get the complete schedule of immunizations recommended by the CDC) • The good news—the prevention of childhood diseases… the bad news? Most of the vaccines are needles, so…in the future… • Shampoos as vaccines? • Nano-bandaids Vaccine miracles…meningitis in kids • H. flu meningitis—what are the numbers? 40-100 cases/100,000 of invasive H. flu in 1989; vaccine in 1990— • 1.4 cases/100,000 today • Strep pneumoniae meningitis—what are the numbers? 77% decline in kids; 60% decline in adults via “herd immunity” • Lumbar punctures in kids—before, during, after…too many… Why do we need vaccine boosters? • To boost the immune system’s memory… • Boosters for kids, boosters for adults • One shot, two shots or three shots? Depends on the response of the immune system (rethinking the 3 HPV shots…may only need 2) • Pneumococcal vaccine at age 65; repeat in 5-7 years • Give it earlier in patients with chronic disease Tetanus (lockjaw)/diphtheria booster • Td (tetanus toxoid, reduced diphtheria toxoid) – every 10 years • Why every 10 years? The diphtheria portion wears off in 11 years; the tetanus doesn’t wear off for 19 years…but, since they are given together it is better to err on the safe side and give it every 10 years • What are the two most common causes for tetanus (lockjaw) in the older individual? • Tdap (Td + and acellular pertussis)Boostrix (ages 10-18) and Adacel (ages 11 to 64)— one time booster (over 65 if taking care of infants) So how does the immune system work? • You actually have 2 “immune” systems… • 1) Innate “immune” system—born with certain abilities to fight invading pathogens • 2) Acquired or adaptive “immune” system—you learn from experience—you have to meet the pathogen and respond specifically to it, and then…remember it! INNATE IMMUNE RESPONSE…Barrier defense mechanisms and acute inflammation • Skin and mucous membranes—bleeding gums, ulcerative lesions • Toothbrushes and flossing* (dental prophylaxis w/antibiotics) • How do we, as HCPs, disrupt the immune system in patients? We break the barriers… • Gotta hole? We’ll put a tube in it…if you don’t have a hole for the tube we’re holding—we’ll make a new hole for ya’! Urinary catheters, Hickman catheters, ports, arterial lines, venous lines, surgical sites, J tubes, G tubes, IV tubes, trach tubes Barrier defenses • Saliva—protective factors including the antibody secreted in saliva, IgA. • And saliva has a low salinity (drugs that are anticholinergic increase the risk for infections by making the mouth dry) pH of body fluids—gastric acid • acid pH of 2 in the stomach keeps a lot of bugs “out” • Therapy with PPIs (the “prazoles”), H2 blockers (the “tidines”), and antacids have been associated with an increased risk of hospitalacquired pneumonia (JAMA 2009;301:2120-2128); • increased risk of C. difficile with PPIs Re-evaluate certain prescribing patterns for chronic conditions – PPIs (proton pump inhibitors) for GERD • Up to 70% of PPI use is unnecessary (Archives of Internal Medicine 2010;170:784-790, 772-778) • One Clostridium difficile infection for every 67 hospitalized patients using a PPI for 2 weeks • Daily PPI use is associated with an estimated 74% increase in C. diff infection • People using PPIs while being treated for C. diff had a 42 % increased risk of recurrence Use of PPIs and clostridium difficile • Should all patients be put on PPIs upon admission to the hospital? NO, it’s NOT necessary… • ICU patients? YES, because they have been shown to have the highest risk for a GI bleed from stress-induced gastric ulcers; • But NO for every bunionectomy, hemorrhoidectomy, or tonsillectomy • Reid M et all. Inappropriate prescribing of proton pump inhibitors in hospitalized patients. J Hosp Med 2012 May/Jun 7:421; • Herzig SJ et al. Acid-suppressive medication use and the risk for nosocomial gastrointestinal tract bleeding. Arch Intern Med 2011 Jun 13;171:991 JUST AS IMPORTANT… • Check the hospital discharge orders…have they been sent home or to the LTCF on a PPI for NO apparent clinical reason? • Make SURE PPIs used in the hospital for ulcer prophylaxis are discontinued (Prescriber’s Letter, April 2016) Recommended time frames for PPI use • Who needs longer term use? Chronic NSAID use, Barrett’s esophagus, anti-coagulant use after a GI bleed • Use the lowest effective dose for long-term use—if stopping the PPI after long-term use, taper the dose over 4-6 weeks to prevent acid rebound – lower the dose every week, then increase the dosing interval to every other day, every third day; • Can use a short course if symptoms return after stopping a PPI • (Prescriber’s Letter, April 2016) Urinary pH • The urethra has estrogen receptors on it; estrogen helps prevent the attachment of bacteria to the urethra and bladder • estrogen also helps to maintain an acid pH to keep pathogens OUT • Young girls and old gals have more alkaline urinary pH due to estrogen deficiency Estrogen to prevent urinary tract infections • Prophylaxis with daily topical estrogen vaginal cream to treat atrophic vaginitis demonstrates a 50% reduction in UTI; oral estrogens are less effective • Premarin vaginal cream, vagifem suppositories, Estring • Prophylaxis with daily cranberry tablets may reduce the risk of future UTIs in premenopausal women, but data are conflicting (? PMF) • Less evidence for intravaginal and oral Lactobacillus probiotics • Arnold JJ, Hehn LE, Klein DA Common Questions About Recurrent UTIs in Women. Am Family Phys 2016 Apr 1;93(7):560 Vaginal pH • Yeast infections • When the estrogen levels are low or non-existent • Antibiotics change the pH and normal flora of the vagina • “You have a yeast infection….” Innate defense: acute inflammation • Inflammation • Vasodilation • Increased permeability of vascular membranes • Arrival of WBCs—first the neutrophils and then the macrophages Acute inflammation—white blood cells • Segs, also known as (neutrophils) are the cells of acute inflammation—comprise 60% of the total WBC and differential; immature segs are called “bands”—normal bands comprise 0-4% of the total white count • Segs and bands respond to acute tissue necrosis and acute bacterial invasion within 5 to 10 minutes of tissue damage or invasion; total WBC increases within 4 hours • Also respond to a signal from the specific immune response—(more later) • Unfortunately, in autoimmune disease, the neutrophils play a major role in destruction of tissues such as the joints in patients with rheumatoid arthritis; in the kidneys in patients with lupus SEGS…margination, pavementing, migration, engulfment, and degranulation • Margination, pavementing, migration and engulfment and degranulation (release of preformed granules) • Marginating segs (measured by WBC count) • Pavementing segs (stuck to walls) Yum Prednisone is a potent anti-inflammatory drug • Prednisone is a corticosteroid; • It inhibits migration, engulfment and degranulation of the neutrophil; hence, its potent anti-inflammatory properties • Why do we use Prednisone with autoimmune disease? For two reasons: • 1) To inhibit the damage caused by one’s own neutrophils attacking various tissues • 2) to suppress the immune response and suppress the production of antibodies against “self”—more in a moment… Prednisone and side effects • High-dose prednisone causes the breakdown of stored glycogen (glycogenolysis)—increases blood sugar and can contribute to secondary diabetes; • One way to prevent this is to co-administer glucophage/metformin with Prednisone; prednisone triggers glycogenolysis in the liver, metformin inhibits glycogenolysis— • The two drugs negate one another in the liver and blood sugars don’t go up So, prednisone is a very popular drug used in patients with autoimmune diseases • Prednisone prednisone > 7.5 mg/day or equivalent for greater than 6 months causes calcium to leave trabecular bone and increases the risk of osteopenia/osteopororis • Risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. • Overall, there were statistically significant treatment effects on bone mineral density at 12 months at the lumbar spine femoral neck, and trochanter. Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group. Other conditions with neutrophils • Blood sugars greater than 180 mg/dL (9.9 mmol/L) inhibit neutrophil migration (diabetics, high blood sugars and infections) • Elderly with decreased migration of neutrophils increases infection susceptibility • Fever increases the migration of neutrophils—is fever good for you? YES! STRESS increases neutrophils • Stress and the WBC—high cortisol levels • Screaming kids • 24-hours post-op • Last trimester of pregnancy • No bands The cells of chronic inflammation and the cells that process and present antigens are: • Monocytes in blood, macrophages (big eater) in tissues • Macrophages have other names in various tissues—microglial cells in the central nervous system, Kupffer cells in the liver, histiocytes in connective tissue • Langerhans cells are also specialized antigen processing cells subepithelial layers of the skin The macrophage—the cell of chronic inflammation and the APC • The macrophage is the antigen processing and presenting cell • Immune cells are “labeled” for identification – using a classification “CD” for cell determinant and given a # • Macrophages have a CD4 on their cell membrane • The cell of chronic inflammation--these cells respond much slower than the neutrophil (2-4 days vs. 5-10 minutes for the neutrophil, the cell of acute inflammation) • MACRO—BIG; PHAGE—EATER (PIG)It engulfs the pathogen; chews it up and processes it and presents it to the helper T cell (T4 cell) –one of the “effector cells of the immune system” The macrophage releases “cytokines” as it engulfs and presents • Interleukins— “inter”= between and “leukins”—white blood cells (leukocytes); there are 36 of them…SERIOUSLY?? Abbreviated IL-1, IL2, IL-3...get it? Aren’t you happy we won’t be talking about ALL of them? • LOL...(but if you want to stay an extra 3 hours, we can...) • Tumor necrosis factor alpha (TNF-a)—a potent inflammatory mediator • Interferons (IFN)—specifically interferon-gamma • Janus kinases—enzymes Let’s put it all together: Gulp, chew, process, spit, kick… “ON” IL-1 receptor II DR CD4 macrophage with CD4 receptor IL-1 release TNF-a IFN-gamma Janus kinase II DR IL-2 T4 cell CD4 helper T cell with CD4 receptor B s, Ts WBCs STOP: How do drugs influence this immune response – many of which are used to treat autoimmune diseases • Prednisone inhibits IL-1 (interleukin-1) release—immunosuppressive (Lupus, MG, AIHA, ITP, RA as bridging therapy to the longer-acting DMARDs*) • Methotrexate--blocks the binding of interleukin-1 to the interleukin 1 receptor on target cells; inhibits T cell activation • Plaquenil inhibits macrophage function (Lupus) • Cyclosporine inhibits IL-2—used to reduce tissue transplant rejection • Etanercept (Enbrel) binds with excess TNF-a molecules—anti-inflammatory • Janus kinase inhibitors—tofiticinib (Xeljanz) • IL-17A, IL-6, IL-22, IL-23—all inflammatory interleukins-• *DMARDs—disease modifying anti-rheumatic drugs) Langerhan’s cells and IL-17 • IL-17 is a cytokine, which is a protein that controls cells and activates inflammation. • In someone with psoriasis, the signals in the normal healing process of skin due to minor trauma are faulty. The tissue overreacts to an injury in the skin, or the immune system will mobilize for an unknown reason. People with psoriasis lesions, in particular, have 30 times more of the inflammatory interleukin, IL-17, than people without lesions, Bagel et al. August 2012 Practical Dermatology. • Studies have clearly demonstrated that blocking IL-17, or reducing it, can help clear psoriasis. • Secukinumab/Cosyntex – 81% of patients with a 75% improvement in sx How do drugs influence the immune system? • Mycophenolate mofetilCellcept • Verdolizumab-- Entyvio is a humanized (“u”) monoclonal antibody that blocks a protein called alpha-4-beta-7, an integrin on neutrophils and macrophages that cause these cells to adhere to the gastrointestinal tract and trigger inflammation • Integrins are also called adhesion molecules and if you block these molecules activated WBCs can’t enter the GI tract and cause inflammation Monoclonal antibodies (the “li” group) • Adalimumab (Humira), infliximab (Remicade), golimumab (Simponi), certolizumab pegol (Cimzia) block TNF-a • Daclizumab (Zenapax)—blocks IL-2 on activated T cells to prevent organ transplant rejection • Belimumab (Benlysta)—(SLE) targets B lymphocyte stimulator protein HIV and the CD4 cells • The AIDs virus (HIV) enters any cell with a CD4 receptor— takes over the replication of the cell and then destroys the cell after replicating; • HIV is silently and completely destroying the macrophage population in tissues • HIV also kills the circulating CD4 cells; new studies show that starting antiretroviral therapy as soon one is diagnosed can not only improve the patients health and longevity but also decreases the risk and rate of transmission of HIV significantly More on vitamin D and the immune system • • • • • Dramatically stimulates antimicrobial proteins from neutrophils, monocytes, NK cells, and epithelial cells lining the respiratory tract Vitamin D deficiency (less than 40 nmol/L) increases the risk of respiratory tract infections Sicker in the winter? Vitamin D deficiency and autoimmune disease—correlates positively with latitude from the equator—MS, Type 1 DM, IBD Vitamin D and prostate cancer Let’s go back to the cytokines…interleukin 1 and why you feel so yucky when you’re sick • Interleukin-1 used to be known as a pyrogen-• Increases temperature set point by increasing the production and release of prostaglandins in the hypothalamus • A fever recruits white blood cells and makes them more active • A fever decreases the ability of pathogens to utilize iron IL-1 • Increases serotonin release from brainstem—vomiting • Increases serotonin release from the ‘organ of nausea’, the duodenum—nausea IL-1 … • Increases melatonin production and makes you sleepy IL-1 release…fatigue** and sleepiness • Modafinil (Provigil)200/day increased to 400/day at week 3; MS patients with excessive daytime sleepiness • Stankoff B et al.. Neurology 2005 Apr 12; 64:1139-43 • Wingerchuck DM et al. Neurology 2005 Apr 12;64:1267-9 IL-1 release also… • Lowers pain threshold—everything hurts • Your hair hurts • Your teeth hurt • Your skin hurts • You’re tired • You’re miserable… Tumor necrosis factor - alpha • Potent inflammatory mediator • In small doses it’s good for you, in systemic doses it wreaks havoc with joints (Rheumatoid arthritis), with intestines (Crohn’s disease), with skin (psoriasis) • In AIDS patients it’s responsible for “wasting syndrome” Interferon gamma • Boosts immune system • MS and early clinical trials with interferon gamma (if there’s an interferon gamma there has to be an interferon alpha and beta…and YES, there is!—more later) Other chemicals involved in inflammation—anything with the last name -- “itis” • Histamine release from mast cells in tissues—histamine must be a bad guy (anti-histamines) Prostaglandins and inflammation • Prostaglandins are produced daily in certain tissues as a normal part of their function—i.e., the stomach— prostaglandins boost mucus production in the stomach to protect it from the big bad wolf known as acid; • the kidneys—prostaglandins vasodilate the renal afferent arteriole—help to maintain blood flow to the kidney Prostaglandins are also formed with tissue damage • Fall down, go boom and hit your knee and back • INDUCIBLE prostaglandins • OR, when neutrophils attack “self-tissues”—inflammation (autoimmune) Prostaglandins and inflammation • Cyclo-oxygenase is an enzyme necessary for the production of prostaglandins--INFLAMMATION • COX-1—formed with tissue damage as well as daily production in the stomach and in the kidneys to vasodilate the renal arterioles and help renal blood flow (as mentioned earlier) • COX-2—inducible (formed only with tissue damage) • Drugs that block cyclo-oxygenase/prostaglandins can be non-selective (block COX-1 and COX-2) or selective (COX-2) only Drugs that block prostaglandins • Non-selective COX- and COX-2 inhibitors--ASA, most NSAIDS (ibuprofen/Motrin/Advil, naproxen/Aleve/Anaprox, ketoprofen/Orudis, indomethacin/Indocin; ketorolac/Toradol— these can cause GASTRIC ULCERATION by blocking COX – 1 that is necessary to protect the stomach • Selective COX-2 inhibitor (s)--Celecoxib/Celebrex is a pure COX-2 inhibitor; etodolac (Lodine), diclofenac (Voltaren), and meloxicam (Mobic)(Mobicox in Canada are more COX-2 selective Complement and inflammation • Activation of complement (also known as complement fixation)—a series of 9+ inactive proteins responsible for inflammation (activate with tissue damage)— • C1 • C3b (opsonin) coats the foreign pathogen—marking it “to be eaten” by neutrophils and macrophages • C4 • C5a (chemotaxin) calls in macrophages and neutrophils to chow down on “foreign pathogens” including “self • C56789—lysis—marks the cell so that it will “burst” Complement and inflammation • complement levels can be measured during active inflammation— example, lupus and the kidney-- “lupus nephritis”—most commonly measure C3, C4 • With active kidney involvement the complement levels will DECREASE as complement is being “used up” to during the acute inflammatory response Inflammation and Alzheimer’s…the old approach targeting betaamyloid isn’t working • “Alzheimer’s might be the most frustrating graveyard in pharmaceutical research and development.” • NEW APPROACH? Make antibodies that inhibit a protein called C1q. What is C1q? It’s a protein found in the complement pathway, which is an important part of the innate immune system. This complement protein helps identify the synapses that need to be “pruned” over the years. Why would we want to “PRUNE” neurons? Don’t we need them ALL? Actually we don’t… • (Annexon, company in South SF started in 2011 by Stanford neurobiologist Ben Barres) A new approach to Alzheimer’s…the old one isn’t working... • The problem, as we age, is that C1q accumulates on synapses and removes ones we need for normal neuronal function. If you can make a targeted antibody to inhibit C1q, then perhaps you can allow the functioning neurons to keep doing their jobs. • Brilliant. Now let’s see how it works. Inflammation and Immunity go Hand-in-Hand • • • • How do the 2 go hand-in-hand? Example: Autoimmune glomerulonephritis Glomerular membrane antigens become “FOREIGN”—the immune system tags the membrane as foreign and signals in inflammatory response to destroy the glomerulus • AUTO-ANTIBODY (Fc)—stimulates neutrophils; other antibodies trigger complement formation (opsonization) Autoimmune diseases • Many autoimmune diseases are manifested by “itis’s” • Rheumatoid Arthritis, uveitis, autoimmune glomerulonephritis, Crohn’s ileitis and colitis, ulcerative colitis, Hashimoto’s thyroiditis, polymyositis, dermatomyositis, lupus pericarditis, lupus pleuritis, lupus vasculitis, lupus myocarditis, lupus nephritis AND NOW? The actual cells of the immune system--lymphocytes Cell determinants (CD) on immune cells—flow cytometry test can give absolute #s of Ts, Bs, NK cells • CD3 – found on all T cells • CD4—found on Helper T cells (and don’t forget macrophages) • CD4, CD25—(T regs or regulatory T cells)—dampen down the immune response (used to be called Suppressor T cells) • CD20—found on B lymphocytes; the monoclonal antibody, rituximab/Rituxan), targets this cell determinant—RX for non-Hodgkin’s lymphoma and autoimmune diseases (lupus & others) • CD21—found on B lymphocytes (Epstein Barr virus enters the B lymphocytes via this cell determinant/receptor)—and lives in the B lymphocytes FOREVER and EVER • CD56—Natural Killer Cell marker Cell-mediated immunity (CMI) • T4 Helpers—turn the system “on” • Activated T lymphocytes—cytotoxic—attack viruses, fungus’, protozoa, parasites, cancer, transplant tissue, TB • NO T4’s with HIV/AIDS? • Viral infections (CMV, EBV, herpes esophagitis), Fungal infections (cryptosporidiosis), Protozoa (pneumocystis), parasites (toxoplasmosis), cancer (lymphomas) TB skin test—tests the Memory T cell response • • • • Mantoux test Tests whether or not you have been exposed to TB OR you can have a positive test if you have had the BCG vaccine High risk groups for TB are patients and healthcare workers from other countries—India, China, Russia, Romania, Mexico, Philippines • Having had the BCG vaccine as a child in another country does NOT mean that you are protected from TB • Interferon Gamma release assays for TB in BCG+ pts TB and LTCF (long-term care facilities) • All newly admitted residents should receive two-step mantoux/purified protein derivative (PPD) test unless a physician’s statement has been obtained that the resident had a past positive reaction to tuberculin • A PPD is considered positive and a chest X-ray is indicated when a resident has: Interpreting the TB skin test • ≥10 mm of induration • ≥ 5 mm for patients with organ transplants, geriatric patients, other immunosuppressed conditions, HIV +, recent contact of an active TB case or fibrotic changes on CXR T-cells/macrophages release interferons • Interferon alpha (prevents viral attachment to cells)—Intron Alfa to treat hepatitis • Interferon beta (immunosuppressing)--Avonex (interferon beta 1a), Rebif (interferon beta 1a), Betaseron (interferon beta 1b), Plegridy (peginterferon beta-1a) • Interferon gamma (immunoenhancing) B lymphocytes (cells) • B cell---plasma cell – • Plasma cells produce antibodies (aka (immunoglobulins, gamma globulins) • Usually takes 7-21 days to produce antibodies to your FIRST infection with a pathogen or to a vaccine Five types of antibodies Immunophoresis…IgM, IgG, IgA, IgD, IgE + cathode anode - Well in the gel Electrical current running through gel What do antibodies look like? fab and fc components Plasma cells produce antibodies… • IgA—barrier antibody produced in mucous membranes and secreted; saliva, tears, urine, breast milk • How can you boost IgA levels? Humor, exercise, and sex (but not too much.. Immunoglobulins • IgM—1st formed to an infection; fixes complement (inflammation), agglutinates (clumps)—acute titers • IgG—2nd formed; memory; crosses placenta; fixes complement (inflammation); acts as a opsonin (coats); reactivated with latent infection; convalescent titers • Antibody testing during an illness— “acute vs. convalescent titers” IgM (early)? Or IgG (late)? • Have you had this disease or vaccine before? IgG is the antibody of memory • Varicella titers, EBV titers What about IgD? • WHO CARES? • No one knows exactly what it does, so you don’t have to learn it… IgE—the antibody of allergies • Fc component drills a hole in the mast cell—releases primary granules full of histamine • Histamine is responsible for itchy, sneezy, wheezy, coughy, runny… • Localized histamine release? Hives… • Not all hives are IgE mediated! • Histamine is directly released by morphine • Thermal –induced • Exercise induced The one-airway hypothesis—treat the NOSE Systemic histamine release? Anaphylactic shock Lots of causes of anaphylaxis • Foods—peanuts, tree nuts, fish, shellfish, wheat,, tomatoes, strawberries, maple syrup (all age groups); egg, soy and milk (especially kids) • Medications—beta-lactam AB (esp. PCN), radiocontrast media, NSAIDs, ASA, opioids, insulin, protamine, general anesthetics, streptokinase, blood products, immunotherapy • Venom—bee stings, yellow jackets, hornets, wasps, and fire ants • Miscellaneous—latex, seminal fluid, gelatin, menstruation (progesterone fluctuations), hemodialysis, inhaled allergens (horse dander), exercise (in some people, especially right after ingestion of a particular food), idiopathic (Spettel) • Carry 2 epi pens! (they’re CHEAP! RIIIIIGHT???) Husbands • YES!! Some women are anaphylactically allergic to their husbands semen!! YIKES…whaddya do? Hay fever, asthma, allergic rhinitis—the allergic salute • Increased airway reactivity with low vitamin D levels? • Inner city kids? • Vitamin D levels? What are the triggers? • Pollen, ragweed and other airborne particles • Animal dander—cats and dogs • Roach dander What can you do to reduce allergies? • What can you do to reduce allergies? • Get rid of the pet? • Stop sleeping with the enemy? • Give ‘em a bath once a week? • Get the pet BEFORE you have the child Primary immunodeficiencies • IgA deficiency demonstrates recurrent infections in the respiratory, GI, and GU tract • IgM deficiency is rare, but when present it is usually associated with malignancy and autoimmune disorders—pathogens associated with an IgM deficiency include S. aureus, S. pneumoniae, H. influenza, and viral infections • IgG deficiency-- Sinus infections and other respiratory infections, gastrointestinal infections, ear infections, pneumonia, bronchitis, infections that result in sore throat • Rarely, severe and life-threatening infections 10 warning signs of Primary Immunodeficiency 1. 4 or more new ear infections within 1 year 2. 2 or more serious sinus infections in 1 year 3. 2 or more months of antibiotic Rx w/ little effect 4. 2 or more pneumonias within 1 year 5. Failure of an infant to gain weight or grow normally 6. Recurrent deep skin or organ abscesses 7. Persistent thrush in mouth or fungal infection of skin 8. Need for IV antibiotics to clear infections 9. 2 or more deep-seated infections, including septicemia 10. A FH of primary immunodeficiency Lab Tests for Antibodies and other screening tests for immunodeficiency LAB TEST ABNORMAL VALUE NORMAL VALUE IgA Less than 10 mg/dL suggests IgA deficiency 41-368 mg/dL IgM Less than 30 mg/dL suggests IgM deficiency 47-311 mg/dL IgG Less than 589 mg/dL suggests IgG deficiency 673-1734 IgE Greater than 100 IU/mL suggests significantt allergies Less than 91 IU/mL Diphtheria antitoxoid antibody Less than 0.01 IU/mL Greater than 0.01 IU/mL Tetanus antitoxoid antibody Less than 0.01 IU/mL As above Strep pneumoniae IgG (serotype 14) Each serotype less than 0.3 mcg/mL Greater than 0.3 mcg/mL Immune diseases classified into 4 types • Type 1– IgE anaphylactoid type reactions—prototype is hay fever • Type 2—direct cytotoxic destruction of a gland or tissue—B lymphocytes and T lymphocyte cytotoxic reactions to self-tissues; Hashimoto’s thyroiditis is an example • Type 3—antigen-antibody (immune-complex disease)—SLE, RA • Type 4—contact dermatitis Type 1 anaphylactoid (IgE) mediated diseases • Prototype – Hay fever; asthma; allergic rhinitis; • Anaphylactic shock…the systemic release of histamine—vasodilation (bright red), blood pressure drops, bronchoconstriction, may have explosive diarrhea • Triggers? Bee stings, penicillin, various foods (shellfish, peanuts), husbands Type 2 – cytotoxic reactions to self • Hashimoto’s thyroiditis—autoantibodies to thyroglobulin, antimicrosomal antibodies • Multiple sclerosis—anti-myelin basic protein antibodies • Autoimmune hemolytic anemia—anti-RBC antibodies (Coomb’s test positive) • Celiac disease—anti-endomysial antibodies, anti-transglutaminase Type 2 –cytotoxic reactions to self • Myasthenia gravis—antibodies to acetylcholine receptors in the majority of patients; trigger may be the thymus (cells with similar antigens—skeletal muscle-like) • Should the thymus gland be removed? Moving toward an unequivocal yes… Myasthenia Gravis—removal of the thymus gland • Thymectomy for the treatment of myasthenia gravis is based on several lines of evidence that support a central role of the thymus in the pathogenesis of the disease • Thymomas are present in 10%--thymectomy is considered to be mandatory to prevent further spread • ~70% of the remaining patients with myasthenia gravis have hyperplastic thymic changes that are not seen in healthy persons • Wolfe GI et al. Randomized Trial of Thymectomy in Myasthenia Gravis. N Engl J Med 375;6:511 (August 11, 2016) Type 2—cytotoxic reactions to self • Primary biliary cholangitis—cholestatic autoimmune liver disease marked by the progressive lymphocytic destruction of the smallest intralobular bile ducts • Rx: ursodiol (works for about 60%) • Obeticholic acid (accelerated FDA approval on May 27, 2016) Type 3 – antigen/antibody complex diseases • Antigen/antibody complexes land in small vessels and fix complement; trigger inflammation wherever they land • Prototype—systemic lupus erythematosus; antigen is the nucleus of cells/antibody formed to it…combines into an Ag/Ab complex (measured as anti-nuclear antibodies or ANAs) • Rheumatoid arthritis is another immune complex disease Type 4—T cell mediated • Prototype—contact dermatitis • Prototype— “poison ivy” uroshiol is the culprit (may also be the culprit in psoriasis) • “Latex “allergies are usually contact dermatitis -- latex gloves…(wheezing, hives?) Watch out for those Latex condoms! YIKES! An example of a “multifactorial” autoimmune disease • Type 1A diabetes • A virus? Genes and the response to viruses • Approximately 50 genes for type 1A—about half are genes that coordinate the HLA system that helps the body recognize self vs. nonself; explains why other autoimmune diseases are associated w/ T1DM • also genes that mediate the immune response to viruses (explains the viral hypothesis as the trigger) • When do we get the most viruses? Too little sun—vitamin D deficiency? Beta cells of pancreas have vitamin D receptors • Caucasian? Northern European ancestry • Sunphobia • Sunscreen maniac moms • Kids playing inside (the “thumb tribe”) • Regulatory T cell dysfunction • Remember the Coppertone cutie? Too little dirt • The hygiene hypothesis— GUT bacteria may play a role • Germphobic moms • LET THEM EAT DIRT! Cow’s milk too early… • Decreased risk in babies who are breast fed • Increased risk in drinking cow’s milk—is there a protein that aggravates the immune system and triggers diabetes in genetically susceptible individuals? • FINLAND? No cow’s milk until age 2 • Large scale clinical trial called TRIGR, testing this hypothesis and is scheduled for completion in 2017 Thanks…and remember… • “Support bacteria…they’re the only culture some people have…” THANK YOU. • [email protected] • www.barbbancroft.com • Chicago, IL. Bibliography • Allos BM. Association between Campylobacter jejuni infection and Guillain-Barré syndrome. J Infect Dis 1997;Suppl 2:S125-8. • Chen RT et al. The yin and yang of paracetamol and paediatric immunizations. Lancet 2009 Oct 17; 374:1305) • Goodman AA. The Human Body: How We Fail, How We Heal. Lecture transcript, The Great Courses, The Teaching Company. 2007. • Hoffman RL. What lies behind the vitamin D revolution? The Cinical Advisor 2010 (March); 3136) • Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 8th edition. 2010. Saunders. • Rituximab Protects Insulin Producing Cells in Diabetes—www.MedPageToday.com; November 25, 2009. • Prymula R et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: Two open-label, randomised controlled trials. Lancet 2009 Oct 17; 374:1339 Bibliography • Schaffner W, Jones, TF. Immunizing older adults against tetanus and diptheria. Patient Care 2004 (October); 19-22. • Spettel CA. Anaphylaxis Alert. ADVANCE for NPs, November 2009; 45-52. • Stites DP, Terr AI, Parslow TG. Basic & Clinical Immunology. 8th edition. 1994 • The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Major clinical outcomes in antiretroviral therapy (ART)-naïve participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008 Apr 15;197:1133. • Wejse C et al. Vitamin D as supplementary treatment for tuberculosis; A doubleblind, randomised, placebo-controlled trial. Am J Respir Crit Care Med 2009 May 1;179:843.