MHAM

COLLEGE OF MEDICINE CLASS 2024

Diseases of the Immune System (Part 2)
Dr. Abelardo Alera | September 16, 2021
GENERAL PATHOLOGY

Outline
I. Cell-Mediated Immunity
II. Immunology
A. Disorders of the Immune System
B. Autoimmune Disorders
III. Autoimmune Diseases
A. Tolerance
B. General Features of Autoimmune Diseases

LEGENDS
Presentations remember lecturer previous
exams

Our antibodies are needed for neutralization,

⭐ HUMORAL- CELL - opsonization, antibody dependent cytotoxicity,
MEDIATED MEDIATED activation of complement, lysis of microbes.
IMMUNITY IMMUNITY Finally, the complement is responsible for
Inflammatory reaction
MECHANISM Antibody - Cell - Mediated
mediated CELL-MEDIATED IMMUNITY
CELL TYPE B T Lymphocytes
Lymphocytes

MODE OF Antibodies Direct cell-to-

ACTION circulating in cell contact or
serum secreted
soluble
products (e.g.
cytokines)

PURPOSE Primary Primary

defense defense against
against intracellular
extracellular pathogens:
pathogens: viruses and
fungi,
Extracellular intracellular
bacteria, bacteria, (also
Circulating tumor antigens,
virus and graft
rejection)

It is important to remember the end point. The

cytokines, inflammation, and most important of all is
if there are affected cells, then they need to be
removed from the body

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The soldiers of the body: RBCs and WBCs.
Molecules of the inflammatory response (i.e.,
interleukin causing fever). Every time we don’t feel
well, that is the response of the immune system
telling us to go to bed and rest. The body will then be
able to get rid of the infection. So, one of the best
treatments for infection is bed rest
For cellular response, there are helper T cells (CD4)
and regulatory T cells (CD8)
GENPATH TRANS 1.05| Trans Team: Alinoor, Banuag, Baunto, Haghiri, Macaayan, Macabangon, Nadera, Pantao, Rasul | Editor: Alcuitas, Alvarez, Bernadez
Remember the function of cytokines. Allergy =
interleukin-5 (IL-5)
Intracellular pathogens = Interferon gamma
(special against TB)
Hypersensitivity reaction (allergic reaction in
layman’s term) is the result of the overacting immune
response to internal and external causes.
Hypersensitivity reactions, such as painful
abdomen, cough, asthma, and atopic dermatitis, are
caused by something in the environment. Most of the
time, this is caused by stress. The best remedy for
medical students is not to pursue medicine and find
another career
• Types of hypersensitivity reactions
a. Type 1: Allergic reaction, immediate;
remember IgE
b. Type 2: Antibody-mediated
c. Type 3: Immune complex-mediated
d. Type 4: Cell-mediated; remember
TB, poison ivy, and contact dermatitis
What is the mechanism for SLE?
In SLE, there is an antigen-antibody complex. This
is going to be deposited in the skin of the face
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resulting in a malar rash. If this is deposited in the → A poorly understood disorder having
kidney, you will have a dead patient immunologic association
→ Abnormal proteins that are Immunologic
SLE is an example of type 3 hypersensitivity in origin
IgE attaches to the mast cells which will then release
vasoactive amines (histamines) responsible for all of AUTOIMMUNE DISORDERS
our allergic reactions.

Arthus reaction is common among farmers. This is

a form of serum sickness, a type 3 hypersensitivity
reaction. Before, toxins were injected into horses.
They will then develop antitoxins. The serum will
later be extracted from horses. Once brought into the
patients’ body, they will then produce allergic
reactions. This is why horses are no longer used as
sources of antitoxins.

IMMUNOLOGY
Rheumatoid arthritis is not related to the aging
process.
If arthritis is a result of the aging process, it’s
called osteoarthritis, also known as DJD
(degenerative joint disease).

• Ulcerative Colitis is an inflammatory bowel

disease (IBD) that causes inflammation and
ulcers (sores) in your digestive tract.
Ulcerative colitis affects the innermost lining
of your large intestine (colon) and rectum.
Symptoms usually develop over time, rather
than suddenly.

Our soldiers and policemen should not harm normal • Crohn's disease is a type of inflammatory
cells, if they do otherwise, this is now what we call bowel disease (IBD). It causes inflammation
as autoimmune disease of your digestive tract, which can lead to
abdominal pain, severe diarrhea, fatigue,
DISORDERS OF THE IMMUNE SYSTEM weight loss and malnutrition. In Crohn's
• Hypersensitivity reactions disease, there are healthy parts of the
→ Gives rise to immunologic injury in a intestine mixed in between inflamed areas.
variety of diseases
• Autoimmune diseases • Humoral Response: is also called
→ Caused by immune reactions against
antibody-mediated immunity. With
self.
→ The soldiers and policemen are killing
assistance from helper T cells, B cells will
normal tissue differentiate into plasma B cells that can
• Immunologic deficiency syndromes: produce antibodies against a specific
→ Result from genetically determined or antigen. The humoral immune system deals
acquired defects in some components of with antigens from pathogens that are freely
normal immune system. circulating, or outside the infected cells.
→ Two ways: primary and secondary Antibodies produced by the B cells will bind
• Amyloidosis: to antigens, neutralizing them, or causing
lysis or phagocytosis.
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 o clinical manifestations are
• Cellular Response: occurs inside infected based on certain parameters.
cells and is mediated by T lymphocytes. The
pathogen's antigens are expressed on the
cell surface or on an antigen-presenting cell.
Helper T cells release cytokines that help
activated T cells bind to the infected cells’
MHC-antigen complex and differentiate the
T cell into a cytotoxic T cell. The infected cell
then undergoes lysis.

• Innate Immunity (General)- is the body's
first line of defense against germs entering
the body. It responds in the same way to all
germs and foreign substances, which is why
it is sometimes referred to as the
"nonspecific" immune system. It acts very
quickly
The immune response is favorable when it protects
us against infections or cancer. It is
• Erythroblastosis Fetalis
→ An autoimmune disorder where the
mother is Rhesus negative and the baby
is Rhesus Positive, a serious damage to
the baby.

• Adaptive Immunity, (Specialized)- is also

referred to as acquired immunity or
specific immunity and is only found in
vertebrates. The adaptive immune
response is specific to the pathogen
presented. The adaptive immune response
is meant to attack non-self pathogens but
can sometimes make errors and attack
itself.

Mother Theresa Effect

If patients always volunteer to help the doctors
in the clinics, that patient will have increased IgA Things to remember:
(antibodies found in our mucosa). Problems with blood cells are caused by
With increased IgA, the GIT will be protected autoimmune reactions (i.e., patients with SLE will
from organisms that cause gastroenteritis. have anemia)

Hygiene Theory Dengue fever = autoimmune thrombocytopenia

People who were not exposed to microbes
when they were young have a higher risk of Three antibodies associated with Graves’
getting autoimmune diseases later on in their Disease:
life. 1. TRAb-Thyrotropin receptor antibodies.
2. TPOAb- Thyroid peroxidase antibodies.
3. TgAb- Thyroglobulin antibodies.
Specific Learning Objectives:
• Given a clinical case involving autoimmune
disorders, differentiate each case according
to:
• Types, causes, pathogenesis,
morphology, clinical manifestations,
laboratory diagnosis, prognosis, and
general management.

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 • Immunological tolerance
→ The body will not kill its own cells
→ Unresponsiveness to an antigen as a
result of exposure of the lymphocyte to
that antigen.
• Self-tolerance
→ Unresponsiveness to an individual's own
antigen.
• Autoimmune Disease
→ loss of self-tolerance
→ Can be Organ-specific (i.e., Myasthenia
gravis, Graves’ disease) or systemic
(i.e.SLE- similar to pancytopenia, where
antibodies are against DNA, RBC,
• The most common autoimmune disease is platelets)
Graves’ Disease.
• Patients with Graves’ disease will Points to ponder: students should have passion,
exhibit hypothyroidism and goiter competence, and excellence. Bright students always
excel.
(enlarged thyroid gland).

• Myasthenia Gravis
→ Acetylcholine is destroyed by
autoantibodies
→ In the morning the patient is active and
in the afternoon, his motor function is Thyroid gland = Graves’ Disease
getting weaker and weaker. Nerves = Multiple Sclerosis
Muscles = Myasthenia Gravis
AUTOIMMUNE DIESEASES
• Normal cells are killed TOLERANCE
• Difficult to diagnose → Means we will not be bothered
• Can sometimes only be diagnosed if common
diseases are removed and the following are 1. Central tolerance
still found: → In the higher level of the body
1. Immune reaction specific for self-antigen → Immature self-reactive T or B lymphocyte
2. Reaction is not due to tissue damage clones that recognized self-antigen during
3. Absence of a well-defined cause of the their maturation (generative lymphoid
disease organ) are killed or rendered harmless
via apoptosis
→ Negative selection or deletion

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 2. Peripheral tolerance 1 → not usually involved in inflammatory
→ Towards the outer portions of the body reaction (testis, eye, brain)
→ B cells recognize self-antigen gene → Self Ag are released during trauma or
expresses new antigen receptors, infection
receptor-editing. If not edited, the B cell → In prolonged inflammation - uveitis,
dies by apoptosis orchitis
They attack the normal cell because of the
receptor and the body is going to do • Sympathetic Ophthalmia
something and this is receptor-editing. If → Bilateral, diffuse granulomatous, non-
they are not killed, then the binding site is necrotizing panuveitis
going to be removed so that they can no → Autoimmune inflammatory response
longer harm the normal cells. In the toward ocular antigens- delayed
process, B cells also die by apoptosis. hypersensitivity to melanin containing
structures
Peripheral Tolerance 2 → Occurs after surgery or trauma to an eye
→ Anergy - prolonged or irreversible → 2% of uveitis cases
functional inactivation of lymphocytes → Anterior Uveitis: mutton fat KPs, PS,
induced by encounter with antigen. 2nd thickening of iris from lymphocytic
signal CD28 receptor on T cell binds with infiltration
APC costimulatory B7-1, B7-2 → Posterior uveitis, dalen-fuchs nodules,
When is this going to happen? peripapillary choroidal lesions, exudative
We need a co-simulator for them to RD
become active.
→ Weak or no co-`stimulator cell are What will happen to the right eye if it is poked
rendered anergic (resting APC in normal with a pencil?
tissue) → Blind (not functional). It becomes
permanently damaged. Eyes are not
Peripheral Tolerance 3 usually touched by inflammatory
→ Suppression by regulatory T cells reactions. However, the other normal eye
→ If there is central apoptosis, then there is will be attacked by autoantibodies. The
going to be a peripheral tolerance. If there other uninvolved eye will be damaged
is a form of inflammatory reaction, and it by an autoimmune reaction
shouldn’t be there, it should be removed. (Sympathetic Ophthalmia). As a result,
What are the ways to remove it? you become totally blind.
Inhibitory stimulation IL-10, TGF-beta-
inhibit lymphocyte activation and effector
functions.
→ Lymphocyte function: destroy things that
shouldn’t be there
→ Immunosuppressive cytokines IL-10,
TGF-beta- inhibit lymphocyte activation
and effector functions

Peripheral Tolerance 4
→ Deletion by activation of induced cell
death - lymphocyte that recognize self-
antigen receives signal that promotes
apoptosis MECHANISMS OF AUTOIMMUNITY
→ Apoptosis stops lymphocytes from • Combination of inheritance of susceptibility
creating immune response that must not genes (breakdown of self-tolerance) and
be happening among healthy tissues environment triggers (infection and tissue
damage)
• Peripheral Tolerance
→ “Sequestered antigen”- immune
privilege sites

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• PTPN-22
→ Gene most frequently implicated in
autoimmune-associated RA and type 1 DM,
abnormal gene NOD-2 (Crohn Disease)

Problem especially if dealing with SLE: genes or

breakdown of tolerance

Costimulator is responsible for causing

autoantibodies

Role of Infection 1
• Mechanism of autoimmunity
→ EBV and HIV -> polyclonial B cell
activation -> production of
Look at genetic abnormality plus the problems in the autoantibodies
environment like infections or tissue damage. This is → In developing countries, infection
going to cause resurgence of lymphocytes that are protects against autoimmune
going to destroy normal tissues. Ideally this influx disease
needs to be stopped centrally or peripherally → Theory: infection promotes low
(most important: apoptosis) level IL-2 production -> maintain
regulatory T cells
Role of Infection 1
• Mechanism of autoimmunity Remember the Hygiene Theory
→ Infection upregulates expression co KEY CONCEPTS
stimulator of APCs -> activates T cell.
→ Microbes express antigen similar to self-
antigen, “molecular mimicry”- post strep
myocarditis
→ Molecular mimicry: for instance, the patient
has recurrent sore throat caused by an
organism that has similar protein with that of
the proteins of the heart. Because of this, the
soldiers can't differentiate the normal heart
muscle versus the bacteria (Strep pyogenes)

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 GENERAL FEATURES OF AUTOIMMUNE
DISEASES
• Progressive disorders with relapses and
remission
• Overlapping clinical/pathologic serologic
features
ANA (antinuclear antibodies) = autoimmune
disease; presents as systemic disease
involving blood vessels and CT (formerly known
as collagen vascular disease)

For our UE/bimonthly exam, diagnostic laboratory Problem with a gene: there are defective genes that
tests will be asked. So, ANA (antinuclear loses tolerance
antibodies) for all, its generic, but it's not going to
point the specific disease, like SLE our answer is
double stranded DNA test or smith antigen test,
which are the common laboratories that we can
request for; DNA topoisomerase or centromeric
proteins = systemic sclerosis; SS-A or SS-B =
Sjogren syndrome; CCP = rheumatoid arthritis

• SLE
→ Vast array of autoantibodies (ANA)
→ Chronic limiting relapsing febrile
disorder
→ Injury skin, joints, kidney serosal
membranes
→ Common among females; younger age Familiarize the table
group; related to estrogen
If the question is febrile, the firsts on our Classification: you need to get at least four of the
list are infection, cancer, and don't forget findings to make a diagnosis
the autoimmune diseases. Not all fever
is an infection. It can cause damage to What is the most common clinical manifestation
some of the organs of the body. Best of SLE?
example is the kidney. Hematologic: anemia, thrombocytopenia, and even
leukopenia

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 • Environmental factors
→ UV exacerbates disease, induces
apoptosis, alters DNA
→ others: estrogen, hydralazine,
procainamide, B-penicillamine
In females, the factor causing malar rash,
dyspnea, and anemia is hormonal
(estrogen)

• SLE: Type III hypersensitivity reaction

→ Immune complex deposition- glomerular-
antibodies opsonize RBC, WBC, PI ->
decreased levels of these blood cells
→ Lupus nephritis- 50%
→ Malar rush- 50% (BM
vacuolar degeneration caused by
• SLE deposition of antibody-antigen
→ ANA: positive in almost all cases complexes)
→ Diagnostic test: antibody to double → Joint: little deformity- different from RA
stranded DNA, Sm (smith)
→ Antiphospholipid antibody- 40-50% • SLE
false (+) syphilis serological → Pericarditis- 50%, myocarditis, valvular
examination antibody binds to cardiolipin endocarditis (nonbacterial verrucous
antigen endocarditis)
→ Cause: unknown- failure of mechanism → “Libman-Sacks”
that maintain self-tolerance → Spleen- “onion-skin” lesion, intimal and
smooth muscle hyperplasia
→ Lungs- 50% with effusion

Another thing to remember is, there is involvement

of the heart and the lungs. And if we are going to
have some form of endocarditis, that is nonbacterial.
So the patient presents with valvular endocarditis.
One of the differences aside from bacterial
endocarditis is “Libman-Sacks”. In the spleen we’ll
call it an “onion-skin” lesion. Again, rule of 50. In 50%
of lungs, there are effusion. Patients who are
anemic, female with lung effusion plus
pancytopenia, including problems with the joints,
then do not forget SLE especially if the patient has a
failing kidney.
Another way to look for SLE pattern is by using the
immunofluorescence technique

Rim pattern is classic for SLE

• SLE
→ Genetic factors: inherited deficiency in C2,
C4, C1q (impaired removal of immune
complex)
→ Immunologic factors: failure of self-
tolerance in B cells.
Defective elimination of self-reactive B
cells
If the deficiency is in the complement, the
patient is at risk in getting infection
(Pneumococcus) • Clinical manifestations
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 → Variable presentation
→ (+) ANA 100% cases
→ Psychosis, convulsions
→ Prone to infection -> immune
dysfunction
→ Tx: immunosuppressive drugs ->
flares and remission
→ Cause of death: renal failure,
intercurrent infection

These are the manifestations. Sometimes you think

that patient is psychotic because of mental
problems. There is psychosis in SLE and in typhoid
fever. Those are not mental problems. These are the This is what a Malar Rash would look like. Know
effects of the disease. what is causing this and what is the diagnosis of this.
Immunosuppressive drug is the treatment to stop the
immune response. Unfortunately, there’s going to be
flares and remission. So, the patient is well, the
patient is sick.
Cause of death: don’t forget the kidney. You’ll be
surprised that there are a lot of antibodies, there are
a lot of cells that are killing normal tissues and these
patients are prone to infection because of the
immune response although it's overreacting, it is
dysfunctional. So, it's not as good as a healthy
person’s immune response.

This is the cause of the malar rash. This is using our

microscope. This part here is the deposition of the
antigen antibody complex.

KEY CONCEPTS

This is Michael Jackson. He does not have Malar

Rash.

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 neurons are going to get oxygen from the healthy
neurons, so expect now what is going to happen.
Your healthy neurons are devoid of oxygen -> brain
fog.

• Sjogren syndrome
→ Dry eyes (keratoconjunctivitis sicca)
→ Dry mouth (xerostomia)
→ Causes immunologically mediated
destruction of lacrimal and salivary glands Common salivary tumor is mixed tumor
→ Histology: lymphocytic infiltration and Differential diagnoses: mumps and Sjogren
fibrosis in lacrimal and salivary glands syndrome

Sjogren syndrome is another type. The antibodies

are now going to destroy the secretions, our
secretory glands in the eyes and the mouth. This is
going to cause a lot of lymphocytes in the affected
area.

Look at the antibodies. Viral infections are going to

release self-antigen and it’s going to cause an
inflammatory reaction causing fibrosis. So, the dry
eyes, dry mouth, and the abnormal glands that
cause the secretion are going to be replaced by
fibrous tissue.
These are the two ways that we are going to
remember Sjogren Syndrome. Remember again, for • Sjogren Syndrome
autoimmune disorders, patients have brain → Difficulty of swallowing of solid, dry buccal
problems or brain fog. mucosa, synovitis, diffuse pulmonary
fibrosis, peripheral neuropathy, rare
So how do we explain brain fog in covid, glomerular lesion.
especially those who are chronically affected? → 60% with rheumatoid arthritis (RA)
They have recovered from the COVID infection but → Mikulicz disease – lacrimal and salivary
there are times that they have mental abscess. So, inflammation.
one of the reasons is the cells in our brain (neurons). → the patient will also develop dry
There are two types of neurons if the patient has eyes and will eventually go blind.
COVID infection- normal neurons and neurons → Mikulicz syndrome – enlargement (not
infected with COVID. So, the COVID-infected only due to autoimmune disease), but also
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 due to sarcoidosis, leukemia, lymphoma,
and other tumors.
→ The disease is believed to be caused by
an autoimmune T-cell reaction against an
unknown self antigen expressed in these
glands, or immune reactions against the
antigens of a virus that infects the tissues.
KEY CONCEPTS
• Systemic sclerosis
→ Scleroderma
→ Chronic inflammation due
autoimmunity -> damage small blood
vessels -> perivascular fibrosis of skin,
multiple organs -> GIT, kidneys, heart
muscle, and lungs.
→ Cause of death: renal failure, pulmonary
insufficiency, intestinal malabsorption (if
it involves the GIT),
→ limited disease: fingers, forearms, face
What are the key findings in
malabsorption? How do you describe
the stool if there is malabsorption?
Fatty, bulky, frothy, and foul-smelling
stool, termed as steatorrhea.
Malabsorption causes the loss of
digestive enzymes.
Pathogenesis
1. abnormal immune response ->
unidentified Ag accumulation in skin ->
CD4 T cells release cytokines ->
produce inflammation and fibrosis.
There is fibrosis because there is
aberrant release of cytokines.
• Laboratory Examinations:
1. (+) DNA topoisomerase I ab (anti-Scl 70)
systemic sclerosis 30-70%
2. (+) anticentromere ab limited disease 20-
40%
3. (+) RNA polymerase III ab acute onset 15-
20%
• Pathogenesis
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→ Vascular damage -> narrowing
microvasculature -> ischemic injury -
> scarring
→ Fibrosis
→ Morphology: fingers tapered-claw
like, auto-amputation: remember
that the damage is ischemic
necrosis, followed by scarring.
→ GIT affected 90%, esophagitis,
malabsorption -> damage to villi
and microvilli
→ 2/3 with kidney problem -> 30%
HPN
Notice that there is an overlap for autoimmune
diseases; sometimes it’s difficult to differentiate one
from the other, so look at the clinical presentation,
and most importantly, our laboratory diagnosis.
to
The endpoint is fibrosis. When a blood vessel is
damaged, the result is repair, and a lot of fibrous
tissues are produced, which explains scleroderma.
• Systemic sclerosis
→ Lungs – 50% interstitial fibrosis
→ Pericarditis, effusion, myocardial fibrosis
• Raynaud’s phenomenon
→ Vasoconstriction
→ Dysphagia – esophageal fibrosis
→ The normal lining epithelium of the
esophagus is damaged, replaced by
fibrosis, so there’s problem
swallowing.
→ 50% hypomotility
→ Malignant HPN – ominous sign, may
develop renal failure.
• CREST syndrome
→ limited type of systemic
sclerosis/localized scleroderma
→ Raynaud’s phenomenon
→ Esophageal dysmotility
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 → Sclerodactyly (claw-like)
→ Telangiectasis (blood vessel
malformation)
→ Cause: unknown
→ Autoimmune response: vascular
damage; collagen deposition (effect)

This is the appearance of claw-like fingers; this also

has damage to the blood vessel.

KEY CONCEPTS

• Systemic Sclerosis
→ Systemic sclerosis (commonly called
scleroderma) is characterized by
progressive fibrosis involving the skin,
gastrointestinal tract, and other tissues.
→ Fibrosis may be the result of activation of
fibroblasts by cytokines produced by T
cells, but what triggers T-cell responses is
unknown.
→ Endothelial injury and microvascular
disease are commonly present in the
lesions of systemic sclerosis, perhaps
causing chronic ischemia, but the
pathogenesis of vascular injury is not
known.

• Raynaud's Syndrome Phenomenon

→ Spasm reduces blood flow causing to white

to red to blue (ischemia) coloration with
numbness or pain.
→ Presence of numbness and pain is a sign
of vasculitis, not a good sign.

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