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Immunopathology
Dr. Amitabha Basu MD
OUR TOPIC
1.
2.
3.
TRANSPLANT REJECTION
Graft Vs Host disease
AUTOIMMUNE DISEASES
TRANSPLANT REJECTION and MHC matching
Type of graft.
Mechanism of rejection.
Graft survival.
Complication of
immunosuppression.
Management.
Graft Vs Host reaction.
Type of Grafts
1.
Allograft: An organ or tissue transplanted from one
individual to another of the same species, i.e.
human to human.
2.
Auto graft: Tissue that is taken from one site and
grafted to another site on the same person; "skin
from his thigh replaced the burned skin on his arms“
3.
Xenograft: A xenograft is a transplantation of
tissue from a donor of one species to a recipient of
another species
4.
Fetal tissue grafts: Less chance of reaction.
Mechanism of allograft rejection
1. T cell mediated reaction
a. Involve Cytotoxic T cell ( CD8+)
b. Type IV hypersensitivity reaction
2. Antibody mediated reaction
(mainly ADCC).
When you give a graft…..
• The organ contain
– Tissues of the organ
– Some lymphocytes of the donor
– Some macrophage (APC) of the donor
In the direct pathway,
• Donor class I and class II antigens on APC of the
graft are recognized by CD8+ cytotoxic T cells and
CD4+ helper T cells of host.
• CD4+ cells→ cytokines→ tissue damage by a local
delayed hypersensitivity reaction.
• CD8+ T cells→ kill graft cells
In the indirect pathway
1. Activate macrophage= tissue damage.
2. Form antigen antibody complex and
produce vasculitis= tissue damage.
Types of rejection reaction
1. Hyper acute rejection
2. Acute rejection:
3. Chronic rejection
Hyper acute Acute rejection
↓
↓
Minutes to
hours
Within months
Chronic
rejection
↓
Years
Hyperacute rejection
• Hyperacute rejection occurs when
preformed antidonor antibodies are
present in the circulation of the recipient.
• Morphology: shrunken liver, necrotic
swollen tubular epithelial cell, may show
pyknotic nuclei.
• Scanty bloody urine.
Transplant reaction
Hyper acute
rejection
Acute rejection
Acute
rejection=
rejection
vasculitis
Antibody
mediated.
[localized
Arthus
reaction]
1. Acute
cellular
rejection.
2. Acute
Humoral
rejection.
Fibrinoid necrosis of
arterioles, thrombus in
vessels
Neutrophils in the area.
CD4+ and CD8+ cell in
tissue.
Necrotizing Vasculitis.
And Neutrophils in the
tissue.
Chronic
Rejection
Antibody mediated
vascular damage
Vascular intimal
proliferation.
Kidney change
Hyper acute rejection
kidney rapidly becomes
cyanotic, mottled, and
flaccid and may excrete a
mere few drops of bloody
urine.
Swollen necrotic epithelial
cells.
Management
• Drug cyclosporine (block nuclear factor of
activated T cells- thus inhibit the gene for
IL-2).
• Monoclonal anti-T-cell antibodies (e.g.,
monoclonal anti-CD3 and antibodies
against the IL-2 receptor α chain).
Methods of Increasing Graft Survival
• HLA ( both Class I and class II antigen)
matching in transplants.
• Immunosuppressive therapy.
Survival of grafts: HLA matching in transplants
• HLA matching ( of donor and recipient
cells) for both class I and class II antigens
improves survival:
MHC
MHC
Donor
R
MHC
MHC
=
Good
= Bad
Immunosuppressive therapy
As a method of graft survival
What are the risks?
Complications of Global Immunosuppression
Opportunistic infections:
Pneumocystis
Carinii
Sliver stain.
Cytomegalovirus
(CMV)
pseudohyphae
: Candida
Candida (C. albicans ) infection
Location: skin, mouth,
gastrointestinal tract, and vagina .
Risk : DM and immuno
compromised patient.
Presentation: (thrush-oral).
Gray-white, dirty-looking
pseudomembranes composed of
matted organisms and
inflammatory debris ,
Others
• Risk for developing EBV-induced
lymphomas,
• Human papillomavirus-induced squamous
cell carcinomas, and
• Kaposi sarcoma
Transplantation of Hematopoietic Cells
• Develop Graft vs host reaction.
– GVH disease occurs in any situation in which
immunologically competent cells are
transplanted into immunologically crippled
recipients.
• Example: bone marrow, whole blood.
Mechanism
• Results from the donor lymphocytes attacking the
recipient tissues that has offending HLA antigens.
Host
tissue
Lymphocyte of
donor
[CD8+ cells]
Types
• Acute – days to week
– Donor cells infiltrate host’s epithelia, liver, bile
duct , Gut, lymphnode and dysfunction them.
– Infection – CMV
– Clinical: Jaundice, skin rash, bloody diarrhea,
hepatomegaly heavy infiltration of
lymphocytes in the host tissue.
d/d of acute type of GVH
• Transfusion reaction (TR)
– in contract to GVH, TR occur immediately
after transfusing a mismatched blood.
– ( if you donate A+ blood to a person with B+
blood group etc)
Types
• Chronic – skin atrophy and cholestatic
jaundice.
C/F=GVH disease : Jaundice and Rash,
Time for Autoimmunity
Topic
1.
2.
3.
4.
Immune tolerance
Termination of tolerance
Definition: AUTOIMMUNITY
Mechanisms proposed for development of
autoimmunity
5. Mediators
6. Autoantibody
7. Diseases
Immune tolerance
• A state of unresponsiveness to a specific
antigen or group of antigens to which a
person is normally responsive.
• Self tolerance: Immune tolerance against
self- antigen.
Termination of tolerance
• X-irradiation
• Immunization with cross reactive antigens.
• Autoimmune diseases.
AUTOIMMUNITY
• Autoimmunity can be defined as
breakdown of mechanisms responsible
for self tolerance.
Mechanisms proposed for development of
autoimmunity include:
2
1. Failure of “activation induced death” of
self reactive T cell.
Self reactive T cell
So these T cells kills the cell of our body
in spite they contain self antigen.
Mechanisms proposed for development of
autoimmunity include:
2.
Molecular mimicry ; Some cells of our body share
similar antigen like that of microbes, when
antibodies produced to kill these microbes , they
destroy cells of the body also.
Host
cell
bacteria
Termination of tolerance :
examples (nice to know)
Molecular mimicry:
Rheumatoid
In Streptococcus infection arthritis, Rheumatic
Heart disease.
and EBV infections.
Mediators
• Cytokines.
• Compliments.
Cytokines
• Interleukins
• TNF-alpha
• Interferons
Few examples
• IL-1, TNF-α, type 1 interferons & IL-6:
innate immunity
• IL-2 : Growth factor for T-cells
• IL-12 and IFN-γ: involved in both innate
and adaptive immunity
• IL-10 and TGF-β: down-regulate immune
responses
Cytokines induce their effects in three ways:
• Autocrine effect: IL-2 produced by antigenstimulated T cells stimulates the growth of the same
cells
• Paracrine effect: IL-7 produced by bone marrow or
thymic stromal cells promotes the maturation of Bcell progenitors in the marrow or T-cell precursors in
the thymus, respectively
• Endocrine effect: IL-1 and TNF- produce the
systemic acute-phase response during
inflammation.
• Acute Inflammatory effect: IL1 and IL8.
Autoantibody
• Definition : Antibody against “self
antigen”.
• Mainly against various component of
Nuclei.
• These are celled : Antinuclear Antibodies
(ANA).
ANA DETECTION
A. By estimation of serum titer
B. By staining pattern the tissue.
Disease
ANA
Staining pattern
SLE
Rim and diffuse
dsDNA
MCTD
Speckled
Anti-RNP
PSS
(Scleroderma)
CREST
syndrome
Sjogren's
syndrome
Nucleolar
Scl-70
Centro mere
anti Centromere antibody
SS-A & SS-B
Inflammatory
myopathy
Jo-1
SLE
Diffuse and Rim
Systemic Lupus Erythematosus (SLE)
1. *Skin rash - Malar or
discoid
2. Sensitivity to light
(photo dermatitis)
3. Serositis/synovitis inflammation of serosal
surfaces along with
effusions
Typical skin lesion in SLE
An immunofluorescence micrograph
stained for IgG reveals deposits of
immunoglobulin along
the dermal-epidermal junction.
SLE
4. Glomerulonephritis – Lupus nephritis =
Nephrotic syndrome .
5. *Cytopenias - anemia, leucopenia,
thrombocytopenia.
6. Heart: Libman-Sachs Endocarditis
7. Thrombosis - Antiphospholipid syndrome
(APS) can occur in patients with SLE.
8. Splenomegaly: periarteriolar fibrosis ("onion
skinning") .
SLE
• *Arthritis, fever, weight loss.
• Vasculitis – with fibrinoid necrosis.
Lupus nephritis : Wire loop lesion. Deposit of
C1q occur.
Chronic Discoid Lupus Erythematosus
• Less severe.
• Skin plaques showing varying
degrees of edema, erythema,
scaliness.
• Diagnosis: positive ANA test, but
dsDNA are rarely present.
Drug induced lupus
• Hydralazine, procainamide, INH, and Dpenicillamine.
• Diagnoses:
– Positive antihistone antibodies.
– Negative (mostly( dsDNA).
Diagnosis SLE
1. Antinuclear antibody - rim pattern, anti
double stranded-DNA.
2. Decreased serum complement especially C1q.
Staining patterns in Autoimmune disease.
Nucleolar
Speckled
(PSS)
MCTD
Scleroderma
1.
Progressive Systemic Sclerosis, PSS
2.
Limited scleroderma, or CREST
syndrome.
Scleroderma (Progressive Systemic
Sclerosis, PSS)
• Def : Characterized by excessive fibrosis
in a variety of tissues due to collagen
deposition.
• About 75% of cases are in women, mostly
middle aged.
• Patient may have hypertension.
Scleroderma: dermal fibrosis: no
adenexa seen
Positive for Scl-70
Scleroderma ; reduced figure and
limb movements.
Important clinical feature in PSS
• Skin thickening by fibrosis and collagen
deposition.
• Malignant Hypertension
• And difficulty in swallowing.
Limited scleroderma, or CREST syndrome:
• Positive for anti-Centro mere antibody.
• C = Calcinosis in skin and elsewhere.
• R = Raynaud's phenomenon,
sensitivity to cold.
• E = Esophageal dysmotility from sub
mucosal fibrosis.
• S = Sclerodactyly from dermal
fibrosis.
• T = Telangiectasias .
Calcinosis in skin
Early gangrenous necrosis from vasospasm
with Raynaud's phenomenon.
Sclerodactyly from dermal
fibrosis
Features
Collagen
Deposition
PSS
CREST
Limited areas,
Initial skin
involvement : wide like face and
fingers
spread
Visceral
involvement
Course of
disease
Early and common
Frequent
features
Wide spread Skin
CREST
involvement, malignant
Hypertension and
difficulty in swallowing.
Prognosis
Rapid
Bad
Late and not
common
Benign
Better / benign
course
Sjogren's syndrome
• Autoimmune disease that involves:1. Salivary glands (with xerostomia)
and
2. Lacrimal glands (with
xerophthalmia).
•
Most patients are middle-aged women.
Sjogren's syndrome; salivary gland
histopathology
Diagnosis ; ANA in Sjogren's
syndrome
• The auto antibodies SS-A (Ro) and SS-B
(La).
Sicca syndrome
• Isolated Autoimmune destruction of salivary and
Lacrimal glands.
• This is not common.
• Same ANAs are present like Sjogren syndrome (SS-A
and SS-B)
Inflammatory myopathy
 Polymyositis
1. Common in women
2. Associate with visceral cancer.
3. Symmetric weak-ness of the large
muscles. (difficulty in getting up from the
chair/climbing steps)
4. DIAGNOSIS: Jo-1 autoantibody
Dermatomyositis ( skin + muscle
weakness)
• Clinical feature: Heliotrope Rash
PRIMARY IMMUNODEFICIENCY SYNDROMES
PRIMARY IMMUNODEFICIENCY
SYNDROMES
1. Congenital B- cell deficiency:
1. X-linked Agammaglobulinemia of Bruton
2. Selective IgA Deficiency
3. Common Variable Immunodeficiency
2. Congenital T- cell deficiency
1. DiGeorge Syndrome
2. Wiskott-Aldrich Syndrome
3. Congenital Both B cell and T cell deficiency
1. Severe Combined Immunodeficiency
Key words ; Pathophysiology
Bruton
Disease
Defect in Humoral immunity: B cell defect.
Intact CMI.
Tyrosine kinase deficiency.
DiGeorge
Syndrome
Thymic hypoplasia and T cell defect.
Deletion of Chromosome 22q
WiskottAldrich
Syndrome
SCID
Thymus normal: present with viral and
fungal infection. Thrombocytopenia,
eczema
Both Humoral and cell mediated
depressed.
Adenosine deaminase deficiency.
X-Linked Agammaglobulinemia of Bruton
• Abnormal Ig due to lack of light chain ( abnormal B cell)=
low Ig in serum.
• Seen after 6 months.
• Infection: H. influenzae, S. pneumoniae.
• Pathogenesis: lack of opsonization by Ig but
opsonization by complement may be normal.
• No germinal center in LN.
• Polio vaccination may produce disease!
X-linked Agammaglobulinemia of Bruton
• C/F; Chronic pharyngitis, sinusitis infection with
bacterial organisms (Hemophilus,
Staphylococcus).
• More in male.
• Rarely infection with Virus( because of intact T
cell immunity).
Common Variable Immunodeficiency
• Relatively common a heterogeneous
group of disorders with low Igs.
• They have normal B cell, but they do not
differentiated to plasma cells.
Selective IgA Deficiency: most common
• Incidence:1 in 700
• Asymptomatic.
• Virtual lack of circulating IgA as well as
secretory IgA.
• Increased risk for respiratory,
gastrointestinal (diarrhea).
Severe Combined Immunodeficiency
(SCID)
•
Autosomal recessive: Adenosine
deaminase deficiency. (50 %)
1. No IgM or IgA
2. Ineffective B/T cell.
Severe Combined Immunodeficiency
(SCID)
Morphology:
Lympnnode and Thymic atrophy can occur.
Severe Combined Immunodeficiency
• Some patients develop a skin rash
– shortly after birth owing to transplacental transfer of
maternal T cells or,
– by a blood transfusion that cause GVH disease.
Infants develop
1. Candida skin rashes and thrush,
2. Persistent diarrhea, severe respiratory tract infections
3. Pneumocystis carinii and Pseudomonas soon after birth.
Wiskott-Aldrich Syndrome
• Def: Immunodeficiency with
Thrombocytopenia and Eczema.
• X-linked recessive disease :
thrombocytopenia, eczema, and recurrent
infection, ending in early death.
DiGeorge Syndrome
• Age : Children
• Etiology: Deletion on the long arm of
chromosome 22.
• Pathogenesis :
• Markedly decreased numbers of circulating T
lymphocytes and Thymic hypoplasia.
• T-cell deficiency that results from failure of
development of the third and fourth pharyngeal
pouches
DiGeorge Syndrome : Clinical manifestation
CATCH 22
C = Cardiac defect
A = Abnormal facies
T = Thymic hypoplasia
C = Cleft palate
H = Hypocalcemia
DiGeorge Syndrome : Clinical
features
• Susceptible to fungal and viral infections.
Defective mandible.
Deletion
of chromosome 22.
Key words: clinical features
Bruton
Disease
DiGeorge
Syndrome
SCID
Occur after 6 months.
Commonly bacterial Infection
No viral, fungal infection
Thymus hypoplasia, viral, fungal infection
common.
Thymus and lymph node atrophy, all types
of infections (both bacterial and viral)
Thank you.