IMMUNOLOGY SIMPLIFIED Autoimmune diseases

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IMMUNOLOGY SIMPLIFIEDAutoimmune diseases

• Barb Bancroft, RN, MSN, PNP
• www.barbbancroft.com
• BBancr9271_at_aol.com

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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

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Recognition of SELF vs. Non-SELFMHC (major
histocompatibility complex)

• A small section on chromosome 6 containing a
  group of genes that produce molecules that mark a
  cell as selfcalled 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
  self-antigens are called Human Leukocyte Antigens
  or HLA

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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 werent put on
  tissues solely for the convenience of renal
  transplant surgeons

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General principlesrecognition 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 antigensfound on all body cells (except
  RBCs again) have HLA-A, HLA-B, HLA-Cknown as
  Class I antigens
• Class II antigens known as HLA-DP, HLA-DQ,
  HLA-DR

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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 tissuesAPCs),
  dendritic cells aka Langerhans cells (in skin
  and mucosa just beneath the epithelial
  cellsAPCs), Langerhans cells, B lymphocytes
  (effector cells of the immune system) , activated
  T lymphocytes (effector cells of the immune
  system)
• Antigen Presenting Cellsprocess the foreign
  substance to present to the immune system

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Antigen presenting cell with a Class II HLA-DR
group
Class II --DR
Macrophage Or B lymphocyte Or T lymphocyte
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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 specieshow do lower
  forms of animals meet?

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This is known as clonal selectivity

• Hello, ShirleyIm Duke...yeah, and Im George,
  back here behind Duke...
• Sniff, sniff, sniff, sniff, sniff
• Dogs stick their nose where the sun dont shine
  and say Youre the one for me

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Whoajust checkin
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Why dont we stick our nose where the sun dont
shine? We have a motheryour frontal lobe

• Dont even think about it
• CN 0 The nervus terminalisruns in parallel with
  cranial nerve 1 (the olfactory nerve)

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HLA and autoimmune diseases

• Most autoimmune diseases are associated with
  specific HLA-antigensin other words, an
  individual will inherit specific HLA-antigens
  that predispose that individual to an
  autoimmune disease
• Some of these include
• Rheumatoid Arthritis (HLA-DR1, HLA-DR4)
• Multiple sclerosis (HLA-A8, B8, DR310x greater
  risk)
• Ankylosing spondylitis (HLA-B27)
• Celiac Disease (DQ2, DQ8)

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HLAs and autoimmune disease

• For exampleType 1A diabetesHLA-DR3 (5 risk),
  HLA-DR4 (6 risk), both? (20 risk), and
  DQB1more prevalent in Scandinavians (Finland)
  Blonde-hair, blue-eyed with
• Polyuria (excessive urination), polydipsia
  (excessive drinking), polyphagia (excessive
  eating), weight loss, fatigue

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Historical highlights

• Over a 100 years ago bacteriologist Paul Ehrlich
  coined the term horror autotoxicusa term used
  to describe an immune system attack against a
  persons own tissues. He thought such
  autoimmunityanother term he coinedwas
  biologically possible yet somehow kept in check
• Nobody believed himfast forward--

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Over 80 autoimmune diseases involving
approximately 50 million Americansto name a few

• Rheumaticrheumatoid arthritis, psoriatic
  arthritis
• Neurologicmultiple sclerosis, myasthenia gravis
• VascularKawasaki disease in kids,
  Henoch-Schonlein purpura in kids, ITP in kids
  (immune thrombocytopenic purpura) giant cell
  arteritis (aka temporal arteritis) in adults over
  50
• EndocrineHashimotos thyroiditis, Graves
  disease, Addisons disease, vitiligo
• Dermatologicvitiligo, dermatomyositis, alopecia
  areata, psoriasis
• Gynecologicendometriosis
• ITP in adults lupus or HIV or HCV

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Over 80 autoimmune diseases 50 million Americans

• GICrohn disease, ulcerative colitis, celiac
  disease
• HematologicITP, AIHA (autoimmune hemolytic
  anemia), pernicious anemia
• Multi-systemsystemic lupus erythematosus, MCTD
  (mixed connective tissue disease, polymyositis,
  systemic sclerosis (scleroderma)

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Where theres smoke, theres fire

• Familial clustering (SLE, AIHA, Hashimotos
  thyroiditis)
• Individual with more than one
• Hashimotos Thyroiditis Type 1 DM celiac
• Rheumatoid Arthritis Sjögrens30-50 of
  patients with RA have Sjögrens,
• 8-30 of Systemic Lupus Erythematosus patients
  have systemic sclerosis
• Endometriosis 7x more likely to have
  Hashimotos higher risk for MS, RA, lupus, SS,
  Chronic Fatigue Syndrome (100x), Fibromyalgia
  (2x) (Human Reproduction 2002)

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Raynauds phenomenon

• 1862French 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 Raynauds will ultimately
  have a concomitant disease. Causes include
  connective tissue diseases, such as SLE,
  dermatomyositis, Sjögrens syndrome, RA,
  scleroderma, hypothyroidism
• Calcium channel blockers such as nifedipine
  decrease the frequency of vasospastic events by
  66
• Wigley FM. Clinical Practice. Raynauds
  phenomenon. N Engl J Med 2002 3471001-1008.

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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 throughoutprofound
  fatigue described as debilitating fatigue,
  impacts every aspect of their lives
• HAVE A HIGH INDEX OF SUSCPICION if you are a PCP
  out there!!!

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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
  damageexamples Hashimotos thyroiditis,
  Myasthenia Gravis, Multiple Sclerosis
• On the other end the autoimmune disease can
  damage multiple tissuesin other words, it is
  more systemic (systemic lupus erythematosus)
• And of course, you can something in-between

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Hashimotos thyroiditis

• Anti-microsomal antibodies
• Anti-thyroglobulin antibodies

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Multiple sclerosis

• Antibodies against myelin basic protein in the
  central nervous system
• Optic nervechanges in vision
• Corticospinal tract--spasticity
• Cerebellumbalance and equilibrium
• Spinothalamic tractpain

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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

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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.

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On the other end of the autoimmune spectrum--
systemic lupus erythematosus, SLE or lupus

• LUPUS ERYTHEMATOSUSred wolf
• Auto-antibodies directed DNA components,
  platelets, RBCs, and protein-phospholipid
  complexes results in widespread lesions
  throughout the body
• Affects many systemsskin, musculoskeletal,
  renal, neuropsychiatric, hematologic, renal,
  cardiovascular, pulmonary and reproductive
• 2x greater in black women than white women1/250
  African American women aged 18-65

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In between the single tissue attack vs. the
multisystem attack you have

• Goodpastures 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

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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 _at_ puberty changes microbiome to
  protect male
• Yurkovetsky et al. "Gender bias in autoimmunity
  is influenced by microbiota. Cell Press, August
  22, 2013

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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

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Autoimmune diseasefemale bias

• RA (71) Sjögrens (101) SLE (101)
• Hashimotos thyroiditis (studies vary widely
  from 81 to 251 to 501)
• MG21 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
• MS31

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Autoimmune diseases

• Its NOT just the genespeople 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

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Triggers for genetically-predisposed individuals

• The lack of vitamin D for certain autoimmune
  diseases (T1A DM? MS? Crohns disease?)
• Norovirus and Crohns disease?
• Endogenous triggers? Endogenous enterobacteria
  for Crohns disease and ulcerative colitis?
• Exogenous triggers? Gluten in the diet? Celiac
  disease
• Viruses/ protein in cows milk for T1A DM?
• Multiple environmental factors

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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. 2010201352-60)
• Vitamin D is also used to prevent Type 1 diabetes
  in Finland, and to treat patients with MS and
  Crohn disease

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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

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Campylobacter jejuni and Guillain-Barré syndrome

• A protein (epitope) on C. jejuni is similar to a
  protein on peripheral nervous system
  myelinimmune 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 (lt1 case
  of GBS per 1000 C. jejuni  infections)
• Symptoms occur 3-5 weeks after consuming the
  undercooked chicken
• White meat170 F
• Dark meat and the whole chicken -- 180 F

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Its not just C. jejuni--Other infectious causes
of GBS

• ZIKA virus
• Cytomegalovirus
• Mycoplasma pneumoniae
• Epstein-Barr virus
• Varicella Zoster virus

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Another digressionGuillain-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 reasoneven tho there are 6 serogroups of
  Neisseria meningitidis (A, B, C, X, Y, W-135)the
  vaccine leaves out type B due to antigenic
  mimicry with human polysaccharide in peripheral
  nervous tissue
• NEW group B vaccinesBexsero (given at ages 11
  and 16)doesnt cross-react with peripheral
  myelin (Trumenba approved for ages 10-25)

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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 throatmurmur of mitral
  regurgitation, joint pain, rash

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Rheumatic heart diseasecross 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

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Acute post-streptococcal glomerulonephritis is
another example of molecular mimicry

• M49 is associated with acute post-streptococcal
  glomerulonephritis in genetically susceptible
  individuals

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GABHSpossible cross reaction with basal ganglia
and limbic system

• PANDASPediatric Autoimmune Neuropsychiatric
  disorders associated with Strep
• Tic syndromes OCD
• Sydenhams chorea (St. Vitus Dance)Dr. Thomas
  Sydenham in 17th century

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2nd general principleselectivity and specificity

• The immune system is highly selective and
  specific for each pathogen
• 1 pathogen1 response
• monoclonal

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For example

• How many types of strep are there?
• Over 200 (Group A thru O hemolytic
  propertiesalpha, beta, gamma)Just because you
  have had 1 strep throat doesnt mean youre
  immune to all strep infections--BUMMER
• GABHS (Group A beta hemolytic strep
• Group B strep
• One type of pathogenone response to that
  pathogen
• Known as MONOclonal

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Monoclonal also applies to a class of
drugsmonoclonal 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)

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Monoclonal antibodiesimmune system

• Infliximab (Remicade)targeted against the
  overproduction of the inflammatory product known
  as tumor necrosis factor-alpha (TNF-a), the
  culprit in Crohns disease, Ulcerative colitis,
  Rheumatoid Arthritis, psoriatic arthritis,
  ankylosing spondylitis
• Adalimumab (Humira), certolizumab pegol (Cimzia)

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Monoclonal antibodies

• Rituximab (Rituxan)monoclonal antibody to CD20
  (marker on B lymphocytes)Non-Hodgkins 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)

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3rd general principlememory

• 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.

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There are always exceptions to every rule and
principle

• One big exception the aging immune system tends
  NOT to remember as well

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There are always exceptions to every rule

• Patients on immunosuppressive drugs have immune
  systems that are suppressed and cant remember

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SO, with such a fabulous memory we should never
get the same disease twice! And thats true, MOST
of the time

• HERPES is an exception!! The immune system
  recognizes herpes, responds to herpes, but cant
  KILL it

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The HERPES Family

• HSV-type 1 and HSV-type 2 herpes cold sores
  and herpes genitalia
• VZV (varicella vaccine)shingles, Herpes zoster
• Epstein-Barr virusmono, B-cell lymphoma
• CMVcytomegalovirus gastrointeritis,
  pneumonitis, retinitis, ? Glioblastoma
• HHV-6, HHV-7--rubeola
• KSHV (HHV-8)Kaposis sarcoma (cancer of the
  endothelial cells of the blood vessels)

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Herpes simplex virus--type 1 and 2

• Above and below the belt

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Varicella zoster virus(chickenpox/shingles)

• VZVvaricella zoster virus
• Primary infection is chickenpoxcrawls 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,
  HELLS FIRE

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Immunocompromised? Shingles is the secondary
manifestation

• Hematologic malignancy rate of HZ is 5-25
• Lupus3.2-21
• 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

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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 agingthis
  type of immunity is called cell-mediated immunity
  (CMI) killer T cells are responsible for CMI and
  their action decreases with age

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FYI Percent of individuals with shingles, by age

• 100.5
• 201.3
• 302.7
• 404.8
• 507.5
• 6011.9
• 7019.7
• 8031.8
• 9046.1
• Donahue JG, et al. Archives of Internal Medicine,
  1995.

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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

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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 daysas
  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?

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Vaccine to prevent shinglesZostavax 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 horizonmuch better efficacy

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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
• Burkitts lymphoma
• MONO
• B-cell Lymphoma (the boy in the bubbleDavid
  Vetter)common lymphoma in AIDS patientsas their
  immune systems decline, the EBV reactivates in
  their lymph nodes and triggers uncontrolled
  growth--lymphoma
• Nasopharyngeal carcinoma
• ? MS

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Cytomegalovirus

• CMV (cytomegalovius)gastroenteritis, retinitis,
  pneumonitiswreaks havoc in immuno-compromised
  patients
• Crosses the placenta and can cause cytomegalic
  inclusion disease in developing babies

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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 immunotherapythe use of the
  patients own dendritic cells with a CMV-targeted
  toxin attached and re-infused 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
  patientshowever, 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)

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Two other well-known pathogens (and one other
not-so-well known)the immune system recognizes

• But cant destroy
• LEARN TO PROFILE!
• TBimmigrantsChina, Russia, Romania, India,
  Mexico, Philippines
• Hepatitis CBaby Boomers!! (1945-1965)

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JC Virus (especially important in the
immunocompromised patient)

• JC virus (John Cunningham virus)drugs that
  severely compromise patients (specifically drugs
  for MS, Crohns 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 antibodiesif 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
  201476(6)802-12.

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So lets go back to the MEMORY of the immune
systemhow do you acquire memory?

• You either suffer the infection
• OR YOU

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VACCINATE!!

• VACCINATE, VACCINATE, VACCINATE

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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

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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. memoryvaricella titers,
  CMV titers
• 2) tell us if you have responded to a
  pathogen/vaccine and how strong that response
  was/or currently islevels of titers
• 3) antibodies can tell you something about
  the disease stage (IgM vs. IgGacute phase vs.
  convalescent phase or early vs. memory)more
  later
• 4) antibodies to selfautoimmune antibodies
  to diagnose autoimmune disease
• 5) these titers tend to wane as we agewe
  just cant remember like we used to

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Autoantibodiesmeasuring antibodies to self

• Hashimotos antibodies to components of the
  thyroid glandanti-microsomal antibodies,
  anti-thyroglobulin antibodies
• Type 1A diabetesantibodies 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)anti-mitochondrial antibodies
• Systemic Lupus Erythematosus--auto-antibodies
  are directed at DNA (anti-Nuclear
  antibodies/ANAs, platelets, RBCs, and
  protein-phospholipid complexes

69
Lets get back to vaccines for a
momenthistorical highlights

• Historical highlights
• Chinese vaccines10th century B.C. sowing the
  poxinjecting 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

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Historical Highlights

• 1796--Edward Jenner and the milkmaid--cowpox
  (vacca is the Latin word for cow) offering
  protection against smallpox vacciniacowpox
• His prediction?

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1976last case of smallpox in Somalia

• Small pox
• Great pox
• Chicken pox

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World Health Organization and herd immunity

• Vaccinating 70 of the worlds population against
  smallpox developed herd immunity
• Why were we able to totally eradicate smallpox
  from the face of the earth?

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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 cant 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.

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Herd Immunity

• Herd immunity for polio is 80-86--if you have
  polio you are capable of infecting 5-7 other
  peoplelower herd immunity because it is less
  infectious than measles

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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, blah92 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)

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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 Childrens 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

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The Good Newspoliticians finally wised up

• California Government just passed a law that
  parents cannot opt out for religious/personal
  belief reasonsif they do, they have to home
  school or have private tutors
• Joins WVA and Mississippi with the most strict
  vaccination laws

78
Anti-vaxxers have a new mantratoo many
antigens presented at one time with vaccines

• The smallpox vaccine alone contained 200
  different smallpox specific antigenshad 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

79
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 newsthe prevention of childhood
  diseases the bad news? Most of the vaccines are
  needles, soin the future
• Shampoos as vaccines?
• Nano-bandaids

80
Vaccine miraclesmeningitis in kids

• H. flu meningitiswhat 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 meningitiswhat are the numbers?
  77 decline in kids 60 decline in adults via
  herd immunity
• Lumbar punctures in kidsbefore, during,
  aftertoo many

81
Why do we need vaccine boosters?

• To boost the immune systems 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 shotsmay only need 2)
• Pneumococcal vaccine at age 65 repeat in 5-7
  years
• Give it earlier in patients with chronic disease

82
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 doesnt wear off for
  19 yearsbut, 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)

83
So how does the immune system work?

• You actually have 2 immune systems
• 1) Innate immune systemborn with certain
  abilities to fight invading pathogens
• 2) Acquired or adaptive immune systemyou
  learn from experienceyou have to meet the
  pathogen and respond specifically to it, and
  thenremember it!

84
INNATE IMMUNE RESPONSEBarrier defense mechanisms
and acute inflammation

• Skin and mucous membranesbleeding 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? Well put a tube in itif you dont
  have a hole for the tube were holdingwell 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

85
Barrier defenses

• Salivaprotective 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)

86
pH of body fluidsgastric 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
  hospital-acquired pneumonia (JAMA
  20093012120-2128)
• increased risk of C. difficile with PPIs

87
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 2010170784-790, 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

88
Use of PPIs and clostridium difficile

• Should all patients be put on PPIs upon admission
  to the hospital? NO, its 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 7421
• Herzig SJ et al. Acid-suppressive medication use
  and the risk for nosocomial gastrointestinal
  tract bleeding. Arch Intern Med 2011 Jun
  13171991

89
JUST AS IMPORTANT

• Check the hospital discharge ordershave 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 (Prescribers
  Letter, April 2016)

90
Recommended time frames for PPI use

• Who needs longer term use? Chronic NSAID use,
  Barretts esophagus, anti-coagulant use after a
  GI bleed
• Use the lowest effective dose for long-term
  useif 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
• (Prescribers Letter, April 2016)

91
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

92
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 193(7)560

93
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.

94
Innate defense acute inflammation

• Inflammation
• Vasodilation
• Increased permeability of vascular membranes
• Arrival of WBCsfirst the neutrophils and then
  the macrophages

95
Acute inflammationwhite blood cells

• Segs, also known as (neutrophils) are the cells
  of acute inflammationcomprise 60 of the total
  WBC and differential immature segs are called
  bandsnormal 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

96
SEGSmargination, 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
97
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 ones own
  neutrophils attacking various tissues
• 2) to suppress the immune response and suppress
  the production of antibodies against selfmore
  in a moment

98
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 dont go up

99
So, prednisone is a very popular drug used in
patients with autoimmune diseases

• Prednisone prednisone gt 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.

100
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 neutrophilsis
  fever good for you? YES!

101
STRESS increases neutrophils

• Stress and the WBChigh cortisol levels
• Screaming kids
• 24-hours post-op
• Last trimester of pregnancy
• No bands

102
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
  tissuesmicroglial 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

103
The macrophagethe 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)
• MACROBIG PHAGEEATER (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

104
The macrophage releases cytokines as it engulfs
and presents

• Interleukins inter between and
  leukinswhite blood cells (leukocytes) there
  are 36 of themSERIOUSLY?? Abbreviated IL-1,
  IL-2, IL-3...get it? Arent you happy we wont 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 kinasesenzymes

105
Lets put it all together Gulp, chew, process,
spit, kick
ON
IL-1 receptor
II DR
T4 cell
II DR
IL-2
IL-1 release
B s, Ts WBCs
TNF-a IFN-gamma Janus kinase
CD4
CD4
macrophage with CD4 receptor
helper T cell with CD4 receptor
106
STOP How do drugs influence this immune response
many of which are used to treat autoimmune
diseases

• Prednisone inhibits IL-1 (interleukin-1)
  releaseimmunosuppressive (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-2used to reduce tissue
  transplant rejection
• Etanercept (Enbrel) binds with excess TNF-a
  moleculesanti-inflammatory
• Janus kinase inhibitorstofiticinib (Xeljanz)
• IL-17A, IL-6, IL-22, IL-23all inflammatory
  interleukins--
• DMARDsdisease modifying anti-rheumatic drugs)

107
Langerhans 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

108
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 cant
  enter the GI tract and cause inflammation

109
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

110
HIV and the CD4 cells

• The AIDs virus (HIV) enters any cell with a CD4
  receptortakes 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

111
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
  diseasecorrelates positively with latitude from
  the equatorMS, Type 1 DM, IBD
• Vitamin D and prostate cancer

112
Lets go back to the cytokinesinterleukin 1 and
why you feel so yucky when youre 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

113
IL-1

• Increases serotonin release from
  brainstemvomiting
• Increases serotonin release from the organ of
  nausea, the duodenumnausea

114
IL-1

• Increases melatonin production and makes you
  sleepy

115
IL-1 releasefatigue 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
  641139-43
• Wingerchuck DM et al. Neurology 2005 Apr
  12641267-9

116
IL-1 release also

• Lowers pain thresholdeverything hurts
• Your hair hurts
• Your teeth hurt
• Your skin hurts
• Youre tired
• Youre miserable

117
Tumor necrosis factor - alpha

• Potent inflammatory mediator
• In small doses its good for you, in systemic
  doses it wreaks havoc with joints (Rheumatoid
  arthritis), with intestines (Crohns disease),
  with skin (psoriasis)
• In AIDS patients its responsible for wasting
  syndrome

118
Interferon gamma

• Boosts immune system
• MS and early clinical trials with interferon
  gamma (if theres an interferon gamma there has
  to be an interferon alpha and betaand YES, there
  is!more later)

119
Other chemicals involved in inflammationanything
with the last name -- itis

• Histamine release from mast cells in
  tissueshistamine must be a bad guy
  (anti-histamines)

120
Prostaglandins and inflammation

• Prostaglandins are produced daily in certain
  tissues as a normal part of their functioni.e.,
  the stomachprostaglandins boost mucus production
  in the stomach to protect it from the big bad
  wolf known as acid
• the kidneysprostaglandins vasodilate the renal
  afferent arteriolehelp to maintain blood flow to
  the kidney

121
Prostaglandins are also formed with tissue damage

• Fall down, go boom and hit your knee and back
• INDUCIBLE prostaglandins
• OR, when neutrophils attack self-tissuesinflamm
  ation (autoimmune)

122
Prostaglandins and inflammation

• Cyclo-oxygenase is an enzyme necessary for the
  production of prostaglandins--INFLAMMATION
• COX-1formed 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-2inducible (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

123
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

124
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 pathogenmarking
  it to be eaten by neutrophils and macrophages
• C4
• C5a (chemotaxin) calls in macrophages and
  neutrophils to chow down on foreign pathogens
  including self
• C56789lysismarks the cell so that it will
  burst

125
Complement and inflammation

• complement levels can be measured during active
  inflammationexample, lupus and the kidney--
  lupus nephritismost 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

126
Inflammation and Alzheimersthe old approach
targeting beta-amyloid isnt working

• Alzheimers might be the most frustrating
  graveyard in pharmaceutical research and
  development.
• NEW APPROACH? Make antibodies that inhibit a
  protein called C1q. What is C1q? Its 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? Dont we need
  them ALL? Actually we dont
• (Annexon, company in South SF started in 2011 by
  Stanford neurobiologist Ben Barres)

127
A new approach to Alzheimersthe old one isnt
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 lets see how it works.

128
Inflammation and Immunity go Hand-in-Hand

• How do the 2 go hand-in-hand?
• Example
• Autoimmune glomerulonephritis
• Glomerular membrane antigens become FOREIGNthe
  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)

129
Autoimmune diseases

• Many autoimmune diseases are manifested by
  itiss
• Rheumatoid Arthritis, uveitis, autoimmune
  glomerulonephritis, Crohns ileitis and colitis,
  ulcerative colitis, Hashimotos thyroiditis,
  polymyositis, dermatomyositis, lupus
  pericarditis, lupus pleuritis, lupus vasculitis,
  lupus myocarditis, lupus nephritis

130
AND NOW? The actual cells of the immune
system--lymphocytes
131
Cell determinants (CD) on immune cellsflow
cytometry test can give absolute s of Ts, Bs, NK
cells

• CD3 found on all T cells
• CD4found on Helper T cells (and dont forget
  macrophages)
• CD4, CD25(T regs or regulatory T cells)dampen
  down the immune response (used to be called
  Suppressor T cells)
• CD20found on B lymphocytes the monoclonal
  antibody, rituximab/Rituxan), targets this cell
  determinantRX for non-Hodgkins lymphoma and
  autoimmune diseases (lupus others)
• CD21found on B lymphocytes (Epstein Barr virus
  enters the B lymphocytes via this cell
  determinant/receptor)and lives in the B
  lymphocytes FOREVER and EVER
• CD56Natural Killer Cell marker

132
Cell-mediated immunity (CMI)

• T4 Helpersturn the system on
• Activated T lymphocytescytotoxicattack viruses,
  fungus, protozoa, parasites, cancer, transplant
  tissue, TB
• NO T4s with HIV/AIDS?
• Viral infections (CMV, EBV, herpes esophagitis),
  Fungal infections (cryptosporidiosis), Protozoa
  (pneumocystis), parasites (toxoplasmosis), cancer
  (lymphomas)

133
TB skin testtests 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 countriesIndia,
  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

134
TB and LTCF (long-term care facilities)

• All newly admitted residents should receive
  two-step mantoux/purified protein derivative
  (PPD) test unless a physicians 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

135
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

136
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)

137
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

138
Five types of antibodies ImmunophoresisIgM, IgG,
IgA, IgD, IgE

• cathode
  anode -

Well in the gel
Electrical current running through gel
139
What do antibodies look like?

• Y fab and fc components

140
Plasma cells produce antibodies

• IgAbarrier 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..?

141
Immunoglobulins

• IgM1st formed to an infection fixes complement
  (inflammation), agglutinates (clumps)acute
  titers
• IgG2nd 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

142
What about IgD?

• WHO CARES?
• No one knows exactly what it does, so you dont
  have to learn it

143
IgEthe antibody of allergies

• Fc component drills a hole in the mast
  cellreleases primary granules full of histamine
• Histamine is responsible for itchy, sneezy,
  wheezy, coughy, runny
• Localized histamine release?

144
Hives

• Not all hives are IgE mediated!
• Histamine is directly released by morphine
• Thermal induced
• Exercise induced

145
The one-airway hypothesistreat the NOSE
146
Systemic histamine release? Anaphylactic
shockLots of causes of anaphylaxis

• Foodspeanuts, tree nuts, fish, shellfish,
  wheat,, tomatoes, strawberries, maple syrup (all
  age groups) egg, soy and milk (especially kids)
• Medicationsbeta-lactam AB (esp. PCN),
  radiocontrast media, NSAIDs, ASA, opioids,
  insulin, protamine, general anesthetics,
  streptokinase, blood products, immunotherapy
• Venombee stings, yellow jackets, hornets, wasps,
  and fire ants
• Miscellaneouslatex, 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! (theyre CHEAP! RIIIIIGHT???)

147
Husbands

• YES!! Some women are anaphylactically allergic to
  their husbands semen!! YIKESwhaddya do?

148
Hay fever, asthma, allergic rhinitisthe allergic
salute

• Increased airway reactivity with low vitamin D
  levels?
• Inner city kids?
• Vitamin D levels?

149
What are the triggers?

• Pollen, ragweed and other airborne particles
• Animal dandercats and dogs
• Roach dander

150
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

151
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
  disorderspathogens associated with a