An interactive and easy take on autoimmunity

1. Sometimes the only
happiness one desires is to
hold a brush or pluck
a flower without struggle!

2.  Every pathologist will see such patients!
 There is often a delay in diagnosis (upto 3 yrs!!!)
 Non immunologic derangements often precede
immunologic ones
 Minimum Physician contact time leading to poor
patient advice.
 Correct guidance can save hours of misery and years
of delay

3.  “the scope of pathology is determined only
by the limits a pathologist sets for himself”
 From inter discipline to multi discipline to
cross discipline
 De compartmentalization of scientific
knowledge

4.  A 45 ye old male presented with (2 month
history of)
 Generalized weakness
 Fatigue
 Low grade fever
 No clear diagnosis
 Treated symptomatically
Week 1

5.  Suddenly developed
 Skin eruptions all over the trunk (Suspected drug
reaction?)
 Oral ulcers
 Hospitalized in critical condition..!
Week 2

6.  Extensive investigations but no clear
diagnosis
 Finally tested positive for HIV..!
Week 4

7.  Found to be positive
for HCV
And, then
 Found to be Positive
for HBV as well!!!
 Something wasn’t right!
Week 5

8.  Developed multi organ involvement
 Pleuritis
 Seizures
 Joint pains
 Referred to Oncologist, pulmonologist,
gastroenterologist, Dermatologist, ENT
Specialist…. No clear diagnosis!
Week 7

9.  Finally, someone advised Antinuclear
antibodies which turned out to be positive
 A positive ANA is pathognomonic for SLE
 Patient was traced back and called for
Immunology consult!
 Positive ANA test was reconfirmed by indirect
immunofluorescence testing
Week 9

10.  Diagnosis: SLE
 What actually happened?
 Serum of an SLE patient becomes an
antibody cocktail and the antibody excess
messes up the rapid tests such as Anti HIV
Antibodies , Anti HCV Antibodies, HbsAg
Week 10

11.  As pathologist your index of suspicion
coupled with knowledge can help a relative,
and help in early diagnosis!

16.  Thalassemia in Pakistan
 50,000 - 70000 patients Approx

17.  Systemic Lupus Erythematosus
 42 per 100,000 Disease Burden = 75000
 RheumatoidArthritis
 0.55% Disease Burden = 11,00,000
18

19.  In US, 24 million people have Autoimmune
diseases (Population=370 million, Prevalence
= 6.5%)
 Projected estimates for Pakistan
 6.5% of population
 14300000 people with Autoimmune diseases in
Pakistan (Maybe even more)
 That means what?

20. Population = 11.17 Million
With a 6.5% prevalence of AI diseases
726050 patients

21.  Initial symptoms
 non specific
 Diagnosis
 Delayed
 Missed
 Result: Increased morbidity due to
complications

22.  Example:
 Life time risk for developing Rheumatoid
Arthritis
 1 in 12 for women and 1 in 20 for men
Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset
rheumatoid arthritis and other inflammatory autoimmune rheumatic
diseases. Arthritis Rheum. 2011;63(3):633–639. doi:10.1002/art.30155

24. Reduced
exposure
to
infections
Increased
Allergies
&
Auto
immune
diseases

25.  Protected childhoods
 Don’t play in the mud!
 Sanitized environments
 Overuse of disinfectent soaps, hand washes etc
 Mineral water
 The kids only drink bottled water!!
 Antibiotic over use
 He sneezed… Give him Augmentin
or Cefim right away!

26. Definition:
 Tolerance is specific immunologic
unresponsiveness
 i.e., an immune response to a certain antigen
[or epitope] does not occur, although the
immune system is otherwise functioning
normally

27. Tolerance:
 Lack of reactivity to ‘own’ antigens
 Autoimmune diseases are simply a
break down of tolerance !!
 e.g Systemic Lupus Erythematosus (SLE),
RheumatoidArthritis (RA) etc

28.  “Deletion of self-reactive T-cell precursors
in the thymus”
 In general, antigens that are present during
embryonic life are considered “self ” and do
not stimulate an immunologic response (i.e.,
we are tolerant to those antigens)

29.  T CellTolerance
 B CellTolerance

30.  Types:
 Central tolerance: Thymus
 Mechanism:
▪ Clonal deletion
 Peripheral tolerance: Outside thymus
 Mechanism
▪ Clonal anergy

32.  Peripheral tolerance is necessary because
some antigens are not expressed in the
thymus and therefore some self reactive T
cells are not killed in the thymus.
 There are several mechanisms involved in
peripheral tolerance

34. NormalT Cell Activation In case of clonal anergy

35.  Types:
 Central tolerance: Bone marrow
 Mechanism:
▪ Clonal deletion and receptor editing
 Peripheral tolerance: Outside bone marrow
 Mechanism
▪ Clonal anergy

36.  To avoid clonal deletion , B cells undergo
receptor editing
 Upto 50% of all B cells undergo receptor
editing

37. T CELLS
 Central
 Deletion
 Peripheral
 Anergy
B CELLS
 Central
 Deletion (with
receptor editing)
 Peripheral
 Anergy

38.  Age
 Lower age enhances tolerance
 Structure & dose of antigens
 Lower doses induce tolerance
 Administration of immunosuppressive drugs
 Induces tolerance
 Type of cells involved
 T cells become tolerant more readily
 Administration of a cross-reacting antigen
 Terminates tolerance.

40. Definition
 Loss of tolerance to self antigens

41.  The most important step in the production of
autoimmune disease is the activation of self-
reactive helper (CD4)T cells.
 These self-reactive cells can induce either
cell-mediated or antibody-mediated
autoimmune reactions, respectively

42.  Why are they important?
 A connective tissue disease screening
questionnaire for population studies
(ElizabethW.Karlson, MD)
 https://siteman.wustl.edu/prevention/ydr/

43. These can be:
 Genetic
 Endogenous/ Hormonal
 Environmental

44. The time for life style intervention in autoimmune
diseases is always there

45.  If there’s one in the family, there’d would
more! (Familial clustering!)
 What’s a family?
 Three generation first degree pedigree

48.  HLA genes
 Others

49.  “As many as 25 percent of people with an
autoimmune disease will experience
additional autoimmune disorders”
 Some autoimmune diseases carry an
increased likelihood of having three or more
autoimmune diseases, including rheumatoid
arthritis, multiple sclerosis, Hashimoto's
thyroiditis, and Sjögren’s syndrome

50.  Are not causative
 Only increase likelihood
 What is likelihood, Btw ?

51.  HLA DR4 increases the
chance of having RA by
50%
 HLA DR increases the
incidence of RA from 1
per 1000 population to
2 per 1000 population

54.  Are not causative
 Only increase likelihood
 What is likelihood, Btw ?
 Need an external trigger
 Environmental factors

55.  Environmental causes may account for as
many as 70 percent of all autoimmune
diseases.
 Infections, like the Epstein-Barr virus
 Toxic chemicals, like cigarette smoke
 Dietary factors, like excessive salt

56. Vojdani A, Pollard KM, Campbell AW. Environmental triggers and
autoimmunity. Autoimmune Dis. 2014;2014:798029. doi:10.1155/2014/798029

57.  CMV
 EBV
 ParvoVirus
 Retro viruses (HIV!!)
 HCV….!!!!
 (Inc assoc with thyroid/ pancreatic malfunction)
 Strep Pyogenes
 Rheumatic fever

59.  25% RA associated mortality is due to
infections

60.  90% of all Autoimmune diseases occur in
women
 A lower incidence in men means delayed
diagnosis and less clinical suspicion!!
 What does this mean?

61.  If there is no other identifiable cause, then a
higher index of suspicion is warranted in
 Males with specific symptoms
▪ He has butterfly rash, he cant have SLE possibly
(Yes he has!!)
 Females with general symptoms
▪ (She just has lots of aches and pains, can’t be an
autoimmune disease.. Yes, it might be.. Give her an
autoimmune screen.)

62. For example:
 Smoke
 Cigarette smoke
 (Primary or secondary)
 Smog??
 (Cigarette equivalent of smog)

63.  What’s Rawalpindi’s air
quality equivalence to
cigarette smoke
today?

64.  “Multiple dietary approaches have been
investigated”
 Eat low sugar, moderate fat, high protein,
whole & natural foods cooked in non
inflammatory oils (olive, coconut, canola,
butter)
 Avoid processed foods, sugars, reheated
vegetable or seed oils

65.  A low carb diet helps in
managing AI diseases
(Wahl’s Protocol)
 Vegan diets lower risk
of all cause mortality
(Dr Danielle Belardo,
MD)

66.  Sleep
 Stress
 Exercise
 Mental health

67.  Chronic insomnia is
associated with an
increased incidence of
developing autoimmu
ne disease (Zeilinski et
al)
 One night of poor
sleep causes genome
wide disturbance
(Satchin Panda et al)

68.  Acute as well as long
term stress
predisposes to chronic
conditions including
autoimmune illnesses

69.  In studies, regular exercise has been shown
to help dampen autoimmunity in patients
with lupus, rheumatoid arthritis, multiple
sclerosis, inflammatory bowel disease, and
other conditions.
 Studies have also shown that sedentary
patients have higher incidences
of autoimmune diseases than more active
patients

70.  Something better than nothing
 More is better

71.  Age is just a number
 There are no diseases that should be
considered more acceptable with age
 Diseases are due to sarcopenia, not aging and
sarcopenia is controllable
 More people in US are mobile at 90 than
Pakistani ppl mobile at 70
 Sarcopenia doubles the autoimmunity
related functional dependence

72.  Japanese migrants to US develop lower life
expectancies. Other way round isn’t true.
Why?
 The china study (Hoax or true)
 Longevity
 Health span vs life span
 Why do Mediterranean countries have lower
all cause disease mortality? (Mediterranean
Diet)

73. 1. Molecular mimicry
 Immune response against a substance can induce
immune response against it’s molecular
analogues
2. Alteration of Normal Proteins
3. Release of SequesteredAntigens
 Due to disease etc
4. Epitope Spreading
5. Failure of regulatoryT cells

74.  SLE
 RA
 PemphigusVulgaris
 IDDM
 Grave’s disease
 Coeliac disease

77.  When to screen a patient who has just “aches
and pains” for autoimmune disease?
1. When there is no underlying cause and
general symptoms are not resolving, or
2. a specific symptom develops , or
3. organ involvement becomes apparent

78.  Just getting the autoimmune profile done is
the problem!

79. BASIC SCREEN
 Blood CP
 ESR
 ANA
 ENA Screening
 RA Factor
 C3,C4
 CRP
EXTENDED SCREEN
 Anti ds DNA
 cANCA
 pANCA
 ENA ID

80. DISEASE SPECIFIC
 Anti GBM
 Anti NMDA
 Anti thyroid
 Anti Islet cell
 Anti centromere
 Anti cardiolipin
 Anti beta 2 glycoprotein 1
 etc

MONITORING
 C3, C4
 CRP
 ESR
 ANA/ ANCA

81.  Half life 8 hours
 Best marker of activation of innate immune
response & inflammation
 Indicates
 Infection
 Ongoing inflammation
 Incipient relapse

82.  Half life 6 Days
 Anti IgG, IgM
 An IgM molecule that binds IgG
 Present in majority of systemic autoimmune
illnesses and advancing age
 Reduced in response to treatment

83.  C4 much less than C3 physiologically
 C4 is the first to be depleted
 Best marker of sub clinical autoimmune
pathogenesis
C3 Normal C4 Normal Queisent disease/
normal
C3 Normal C4 reduced Indolent disease/ AI
pathogenesis
C3 reduced C4 reduced Progressive disease

84.  Both ESR, CRP elevated in intractable cases
 ESR raised, normal CRP – Non inflammatory
chronic disease
 ESR normal, raised CRP – infection, acute
disease
 ESR, CRP both normal - Queiscence

85.  Coombs test – Direct/ Indirect
 Anti platelets antibodies
 Anti smooth muscle
 Anti LKM
 Anti Mitochondrial

86.  Most tests are method dependent with varying
sensitivity (esp ANA, ANCA) – High inter and
intra assay reproducibility but questionable inter
method concordance
 Biologic disease precedes clinical disease or vice
versa (Asymptomatic ANA positive or ANA
negatve lupus)
 Undulating course (Test was positive last month,
negative this month, now again positive)
 Treatment target is stopping biologic
progression or clinical disease?

88.  Get a baseline autoimmune screen
 Extended screen in case of baseline positivity
 Repeat at 3 months
 Create a patient profile (Keep & tally the
records)
 Please remember
 Trend more imp than single reading
 Profile more imp than single test

89.  Autoantibodies can cause interference in both
non-immunoassay and immunoassay methods
for a number of analytes
 TFTs,TG, prolactin, other hormones etc
 High /low TFTs, CK, LDH, PRL, etc… Are they real
or interference artifacts…..Serial dilutions is the
solution!
 Conversely, chemistry values reversed by
serial dilutions represent autoantibody
presence

91. https://siteman.wustl.edu/prevention/ydr/
Your personal risk calculator

92. Time for The
mandatory Quiz!!!

93.  Immunologic tolerance is an example of
1. Incomplete immune response
2. Ineffective immune response
3. Partial immune response
4. Absent immune response
5. No immune response

94.  What induces tolerance?
1. Deletion of self reactiveT cells in thymus
2. Deletion of self reactiveT cells in Bone marrow
3. Deletion of self reactive B cells in thymus
4. Deletion of self reactive B cells in Bone marrow

95.  Negative selection ofT cells in thymus is an
example of:
1. Clonal anergy
2. Clonal deletion
3. Receptor editing
4. Breakdown of tolerance
5. None of the above

96.  All of these are mechanisms of peripheralT
cell tolerance except
1. Clonal anergy
2. Clonal deletion
3. Inhibition by regulatoryT cells
4. Positive selection of self reactiveT cells
5. None of the above

97.  All of these are mechanisms of autoimmunity
except:
1. Molecular mimicry
2. Release of Sequestered Antigens
3. Epitope Spreading
4. Failure of regulatoryT cells
5. Negative selection of self reactiveT cells

98.  Following factors are a cause of autoimmune
disease, except:
 Genetic factors
 Hormonal factors
 Environmental factors
 Dietary factors
 None of the above

99. Download the presentation from
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