Transcript IMMUNOLOGY SIMPLIFIED Autoimmune diseases

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…
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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
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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…
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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
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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
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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
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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…
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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”
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*(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.