Dr. Amitabha Basu MD
1. TRANSPLANT REJECTION
2. Graft Vs Host disease
3. AUTOIMMUNE DISEASES
TRANSPLANT REJECTION and MHC matching
Type of graft.
Mechanism of rejection.
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
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
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 Chronic
↓ ↓ rejection
Minutes to Within months Years
• 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
• Scanty bloody urine.
Hyper acute Antibody Fibrinoid necrosis of
rejection mediated. arterioles, thrombus in
Arthus Neutrophils in the area.
Acute rejection 1. Acute CD4+ and CD8+ cell in
Acute 2. Acute Necrotizing Vasculitis.
rejection= Humoral And Neutrophils in the
rejection rejection. tissue.
Chronic Antibody mediated Vascular intimal
Rejection vascular damage proliferation.
Hyper acute rejection kidney rapidly becomes
cyanotic, mottled, and
flaccid and may excrete a
mere few drops of bloody
Swollen necrotic epithelial
• Drug cyclosporine (block nuclear factor of
activated T cells- thus inhibit the gene for
• 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
Donor R = Good
As a method of graft survival
What are the risks?
Complications of Global Immunosuppression
Pneumocystis Cytomegalovirus pseudohyphae
Carinii (CMV) : Candida
Candida (C. albicans ) infection
Location: skin, mouth,
gastrointestinal tract, and vagina .
Risk : DM and immuno
pseudomembranes composed of
matted organisms and
inflammatory debris ,
• Risk for developing EBV-induced
• 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
• Example: bone marrow, whole blood.
• Results from the donor lymphocytes attacking the
recipient tissues that has offending HLA antigens.
• 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)
• Chronic – skin atrophy and cholestatic
C/F=GVH disease : Jaundice and Rash,
Time for Autoimmunity
1. Immune tolerance
2. Termination of tolerance
3. Definition: AUTOIMMUNITY
4. Mechanisms proposed for development of
• A state of unresponsiveness to a specific
antigen or group of antigens to which a
person is normally responsive.
• Self tolerance: Immune tolerance against
Termination of tolerance
• Immunization with cross reactive antigens.
• Autoimmune diseases.
• 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
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.
Termination of tolerance :
examples (nice to know)
Molecular mimicry: Rheumatoid
In Streptococcus infection arthritis, Rheumatic
and EBV infections. Heart disease.
• IL-1, TNF-α, type 1 interferons & IL-6:
• 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
Cytokines induce their effects in three ways:
• Autocrine effect: IL-2 produced by antigen-
stimulated T cells stimulates the growth of the same
• Paracrine effect: IL-7 produced by bone marrow or
thymic stromal cells promotes the maturation of B-
cell 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
• Acute Inflammatory effect: IL1 and IL8.
• Definition : Antibody against “self
• Mainly against various component of
• These are celled : Antinuclear Antibodies
A. By estimation of serum titer
B. By staining pattern the tissue.
Disease Staining pattern ANA
SLE Rim and diffuse dsDNA
MCTD Speckled Anti-RNP
PSS Nucleolar Scl-70
CREST Centro mere anti Centro-
syndrome mere antibody
Sjogren's SS-A & SS-B
Diffuse and Rim
Systemic Lupus Erythematosus (SLE)
1. *Skin rash - Malar or
2. Sensitivity to light
3. Serositis/synovitis -
inflammation of serosal
surfaces along with
Typical skin lesion in SLE
An immunofluorescence micrograph
stained for IgG reveals deposits of
the dermal-epidermal junction.
4. Glomerulonephritis – Lupus nephritis =
Nephrotic syndrome .
5. *Cytopenias - anemia, leucopenia,
6. Heart: Libman-Sachs Endocarditis
7. Thrombosis - Antiphospholipid syndrome
(APS) can occur in patients with SLE.
8. Splenomegaly: periarteriolar fibrosis ("onion
• *Arthritis, fever, weight loss.
• Vasculitis – with fibrinoid necrosis.
Lupus nephritis : Wire loop lesion. Deposit of
Chronic Discoid Lupus Erythematosus
• Less severe.
• Skin plaques showing varying
degrees of edema, erythema,
• Diagnosis: positive ANA test, but
dsDNA are rarely present.
Drug induced lupus
• Hydralazine, procainamide, INH, and D-
– Positive antihistone antibodies.
– Negative (mostly( dsDNA).
1. Antinuclear antibody - rim pattern, anti
2. Decreased serum complement -
Staining patterns in Autoimmune disease.
1. Progressive Systemic Sclerosis, PSS
2. Limited scleroderma, or CREST
Scleroderma (Progressive Systemic
• Def : Characterized by excessive fibrosis
in a variety of tissues due to collagen
• About 75% of cases are in women, mostly
• Patient may have hypertension.
Scleroderma: dermal fibrosis: no
Positive for Scl-70
Scleroderma ; reduced figure and
Important clinical feature in PSS
• Skin thickening by fibrosis and collagen
• 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
• S = Sclerodactyly from dermal
• T = Telangiectasias .
Calcinosis in skin
Early gangrenous necrosis from vasospasm
with Raynaud's phenomenon.
Sclerodactyly from dermal
Features PSS CREST
Collagen Initial skin Limited areas,
Deposition involvement : wide like face and
Visceral Early and common Late and not
Course of Rapid Benign
Frequent Wide spread Skin CREST
features involvement, malignant
difficulty in swallowing.
Prognosis Bad Better / benign
• Autoimmune disease that involves:-
1. Salivary glands (with xerostomia)
2. Lacrimal glands (with
• Most patients are middle-aged women.
Sjogren's syndrome; salivary gland
Diagnosis ; ANA in Sjogren's
• The auto antibodies SS-A (Ro) and SS-B
• Isolated Autoimmune destruction of salivary and
• This is not common.
• Same ANAs are present like Sjogren syndrome (SS-
A and SS-B)
1. Common in women
2. Associate with visceral cancer.
3. Symmetric weak-ness of the large
muscles. (difficulty in getting up from the
4. DIAGNOSIS: Jo-1 autoantibody
Dermatomyositis ( skin + muscle
• Clinical feature: Heliotrope Rash
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 Defect in Humoral immunity: B cell defect.
Disease Intact CMI.
Tyrosine kinase deficiency.
DiGeorge Thymic hypoplasia and T cell defect.
Syndrome Deletion of Chromosome 22q
Wiskott- Thymus normal: present with viral and
Aldrich fungal infection. Thrombocytopenia,
SCID Both Humoral and cell mediated
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,
• More in male.
• Rarely infection with Virus( because of intact T
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
• Virtual lack of circulating IgA as well as
• Increased risk for respiratory,
Severe Combined Immunodeficiency
• Autosomal recessive: Adenosine
deaminase deficiency. (50 %)
1. No IgM or IgA
2. Ineffective B/T cell.
Severe Combined Immunodeficiency
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.
1. Candida skin rashes and thrush,
2. Persistent diarrhea, severe respiratory tract infections
3. Pneumocystis carinii and Pseudomonas soon after birth.
• Def: Immunodeficiency with
Thrombocytopenia and Eczema.
• X-linked recessive disease :
thrombocytopenia, eczema, and recurrent
infection, ending in early death.
• Age : Children
• Etiology: Deletion on the long arm of
• 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
DiGeorge Syndrome : Clinical manifestation
C = Cardiac defect
A = Abnormal facies
T = Thymic hypoplasia
C = Cleft palate
H = Hypocalcemia
DiGeorge Syndrome : Clinical
• Susceptible to fungal and viral infections.
of chromosome 22.
Key words: clinical features
Bruton Occur after 6 months.
Disease Commonly bacterial Infection
No viral, fungal infection
DiGeorge Thymus hypoplasia, viral, fungal infection
SCID Thymus and lymph node atrophy, all types
of infections (both bacterial and viral)