IMMUNOLOGY SIMPLIFIED —from AIDS to ZZZZZZ

IMMUNOLOGY SIMPLIFIED—from AIDS to ZZZZZZ Barb Bancroft, RN, MSN, PNP www.barbbancroft.com BBancr9271@aol.com

Immunology… • Definition: The study of the physiologic mechanisms that allow the body to recognize materials as foreign or abnormal and to neutralize or eliminate those foreign materials.

MHC (major histocompatibility complex) • A small section on chromosome 6 containing a group of genes that produce molecules that mark a cell as “self” • Histocompatibility testing, or tissue typing, involves matching these molecules (antigens) • Because tissue typing is usually performed on White Blood Cells (WBCs), or leukocytes, these self-antigens are called HLA-antigens

HLA antigens… • They were first studied on our WBCs by renal transplant surgeons in the 1960s • All tissues have HLA antigens on them except red blood cells with ABO antigens • Of course, the HLA antigens weren’t put on tissues solely for the convenience of transplant surgeons…

General principles • HLA antigens help the immune system to recognize pathogens and to mount an immune response • All body cells (except RBCs) have HLA-A, HLA-B, HLA-C—known as Class I antigens • HLA-DP, HLA-DQ, HLA-DR—Class II antigens

Class II antigens • Class II antigens are the immune response antigens and are located on only on monocytes (in blood), macrophages (in tissues—APCs*), dendritic cells (in tissues just beneath the epithelial cells—APCs*), B lymphocytes (effector cells of the immune system) , activated T lymphocytes (effector cells of the immune system) • *Antigen processing cells—process the “foreign” substance to present to the immune system

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—you want to select a mate based on “strength” of the immune system—how do lower forms of animals meet? • Clonal selectivity

Clonal selectivity • They stick their nose where the “sun don’t shine” and say… “You’re the one for me…” • Why don’t humans do that? • Well, we kind of do…

When the immune system attacks “self”…specific HLAs are associated with autoimmune disease • For example…Type 1 diabetes—HLA-DR3 (5% risk), HLA-DR4 (6% risk), both? (20% risk)—more prevalent in Scandnavians Blonde-hair, blue-eyed with… Polyuria (excessive urination), Polydipsia (excessive drinking), polyphagia (excessive eating), weight loss, fatigue Named…

Over 80 autoimmune diseases • Most autoimmune diseases associated with specific HLA-antigens include: • Rheumatoid Arthritis (HLA-DR1, HLA-DR4) • Multiple sclerosis (HLA-A8, B8, DR3—10x greater risk) • Celiac Disease (DQ2, DQ8) • What about narcolepsy?

Narcolepsy • Narcolepsy—HLA-DR2 • Stanford University and a breed of Doberman’s

Other HLA and disease associations • Inflammatory diseases such as ankylosing spondylitis and other postinfectious arthropathies (Reiter’s syndrome—HLA-B27 (90-100%) • Inherited errors of metabolism—HLA-A and hereditary hemochromatosis

One more interesting note about autoimmune disease • One in 20 Americans have an autoimmune disorder; 10 times more likely to be female (75%) • RA (7:1); Sjögren’s (9:1); SLE (9:1); MS (3:1); Hashimoto’s (10:1) • Presentation tends to be between 25-45 • Men have an overall increased risk of infectious disease, women have an increased risk of autoimmune disease • Any theories as to why?

Autoimmune disease—loss of self-tolerance • MS—antibodies attack myelin basic protein in the CNS • Guillain-Barré—antibodies attack peripheral nervous system myelin • Systemic Lupus Erythematosus—antibodies attack nuclear proteins—tested by measuring anti-nuclear antibodies (ANAs) • Celiac disease—antibodies attack microvilli of small intestine (especially the duodenum)

Triggers for genetically-predisposed individuals • Some type of trigger – from the outside? (exogenous agent); from the inside? (endogenous agent) • Lack of vitamin D for certain autoimmune diseases (T1 DM, MS?) • Inside triggers? Colonic bacteria and Crohn’s disease/ulcerative colitis? • Outside triggers? Viruses for T1 DM? • Outside triggers? Bacteria (Campylobacter pylori) for Guillain-Barre syndrome?

Cook your chicken! • White meat—170° F • Dark meat -- 180° F • Whole chicken – 180

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) GABHS (Group A beta hemolytic strep— (anti-streptolysin O titers are antibodies made to group A strep) ASO titers and strep throat

Rheumatic heart disease and molecular mimicry • Some infections share epitopes with self-antigens, an immune response against such microbes may produce tissue –damaging reactions that cross react with self-antigens; group A beta hemolytic strep cross reacts with cardiac glycoproteins (myosin-like); takes 7 to 21 days to make antibodies; acute rheumatic heart disease usually occurs 2 to 3 weeks after strep throat—murmur, joint pain, rash

Monoclonal antibodies made in the laboratory— “magic bullets” • Trastuzumab—Herceptin targets the HER/2neu gene in breast cancers; this gene amplifies the growth of the tumor • Rituximab—Rituxan targets a specific protein on B lymphocytes; used for non-Hodgkin’s lymphoma, MS, DM • Cetuximab (Erbitux)—targets epidermal growth factors (Martha Stewart) • Bevacizumab (Avastin)—inhibits angiogenesis (TAF—tumor angiogenesis factor) • Infliximab (Remicade)—targets an inflammatory protein (TNF-a)—Crohn’s disease, rheumatoid arthritis, more…

General Principles 3) 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.

With such a fabulous memory we should never get the same disease twice! BIG exception to the rule… The Herpes “Family” • HSV-type 1 • HSV-type 2 • VZV (varicella vaccine) • Epstein-Barr • CMV • HHV-6, HHV-7 • KSHV (HHV-8) • HUH?

You can’t kill herpes…you can “live with it”… • 3 herpes viruses live in the dorsal root (sensory root) of the peripheral nerves • “What’s the difference between herpes and love?”

Herpes simplex virus--type 1 • HSV-1 typically lives in the dorsal root of the trigeminal nerve • Cold sores • Usually above the belt

Herpes simplex virus—type 2… • HSV- 2—below the belt (STD vs. VD) • “Hey nurse, can I get hairpiece from a toelet seat?”

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 trigeminal nerve (V) • If your immune system is “competent” , the virus remains dormant in the sensory root

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)—multidermatomal shingles • Depression and significant stress within past 6 months increases risk • The elderly

Shingles and the elderly 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 cell-mediated 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.

Locations of Herpes Zoster or “shingles” • 4% sacral • 11% cervical • 13% cranial • 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

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 • ValacyclovirHCl (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 • Vaccine approval May 2006 • 500,000 to 1 million episodes per year • 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

The Epstein-Barr* virus (EBV) is a member of the Herpes “family” • *Dr. Tony Epstein and his lovely assistant, Ms. Yvonne Barr; Denis Burkitt and Burkitt’s lymphoma • Lives in your B lymphocytes • MONO • B-cell Lymphoma (the boy in the bubble—David Vetter) • Nasopharyngeal carcinoma • ? MS

Cytomegalovirus … • CMV (cytomegalovius)—gastroenteritis, retinitis, pneumonitis, adrenalitis, pancreatitis, encephalitis, polyneuritis—wreaks havoc in immunocompromised patients (transplant and HIV+ patients) • Crosses the placenta and can cause cytomegalic inclusion disease in developing babies • ? Trigger of glioblastoma multiforme?

Human herpes virus -6, and Human herpes virus -7 • HHV-6—roseola • HHV-7--???

Human herpes virus-8, or KSHV… • HHV-8 (1995) Kaposi’s Sarcoma Herpes Virus (KSHV) • STD • Rarely found in blood transfusions (only 3 known cases)

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

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 some pathogens and we measure those as “titers”— • Memory T cells directly respond to certain pathogens

How do we test memory? • Antibody titers can do a couple of things: 1) tell us if you have EVER been exposed to a specific pathogen—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) these titers tend to wane as we age—we just can’t remember like we used to…

TB skin 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 are the two top countries • Having had the BCG vaccine as a child in another country does NOT mean that you are protected from TB • Quantiferon Gold test 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:

TB and LTCF • ≥10 mm of induration • ≥ 5 mm for residents with organ transplants, other immunosuppressed conditions, HIV +, recent contact of an active TB case or fibrotic changes on CXR • TB requires airborne precautions, Use of N-95 respirators when entering the room

Let’s get back to vaccines for a moment…historical highlights • Chinese vaccines—11th 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 • Lady Mary WortleyMontegu, wife of the British ambassador to Turkey in the early 1700s, saw it in action and brought the idea back to England from Turkey

Historical Highlights… 1796—English country doctor, 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?

The smallpox vaccine contained 200 different smallpox specific antigens—had the potential to overwhelm the immune system • All vaccines today contain approximately 120 antigens combined

Vaccines… • Prevention of childhood diseases…(kid receive 28 doses 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? • Foods as vaccines?

Using foods as vaccines… • Potatoes • Tomatoes • Bananas • Spinach • Still working on the possibility…

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…

IMMUNOLOGY SIMPLIFIED —from AIDS to ZZZZZZ