Transplant Immunology and Immunodeficiency disease Flashcards
What is Hypersensitivity
Altered immunologic response to an antigen resulting in disease and damage to a host
Types of Hypersensitivity
Allergy
Autoimmunity
Alloimmunity
What is an allergy
deleterious effects of hypersensitivity to environmental (exogenous) antigens
what is Autoimmunity
Disturbance in immunologic tolerance of self-antigens with damage to self tissue
what is Alloimmunity
Immun reaction to tissues of another individual
How is Hypersensitivity characterized
by the immune mechanism
Types of Hypersensitivity
Type I
Type II
Type III
Type IV
type I hypersensitivity
IgE mediated
Type II hypersensitivity
Tissue-specific reactions
Type III hypersensitivity
Immune complex mediated
Type IV hypersensitivity
Cell mediated
When the Immune system reacts with antigens on the tissue of other genetically dissimilar members of the same species
Alloimmunity
When the Fetus expresses parental antigens not found in the mom
Transient neonatal alloimmunity
What are the types of Alloimmunity
Transient neonatal alloimmunity
Transplant rejection
Transfusion reactions
What is MHC essential for
Antigen presentation to T cell
What do T cells look for
Foreign antigens
Self MHC + foreign Ag
T cell response
Self MHC + Self Ag
No t cell response
Where is MHC expressed
it is expressed or can be induced to be expressed on nearly every nucleated cell in the body
MHC I in response to Virus
Viruses can infect virtually any nucleated cells so MHC I fnction to alert the CD8+ T cells
what does MHC expression tell the immune system when it sees a self cell
it says, yo don’t fuck this cell up, its you.
What is a key factor in determining tissue match for transplant donors and recipients
MHC
Specificity of MHC
Many different pepetides can bind within the MHC binding cleft with broad specificity
Binding rate of PEptides to MHC
Slow on and Slow off rate
Do MHC molecules discrimate from self and foreign peptides
NO
what determines which peptides bind and how peptides bind to MHC
MHC haplotypes of an individual
what is MHC also known as
HLA (human Leukocyte antigen)
how many alleles for MHC genes are there
Highly polymorphic (10^13 combinations) as the most polymorphic gene in the human genome
problem with MHC being highly polymorphic
Hard to find transplant donors even under 1st degree relatives
How are MHC alleles expressed
Concomitantly
the set of MHC alleles on an individual chromosome
MHC haplotype
What can the MHC haplotype influence
how an individual responds to certain pathogens
Susceptiblity to certain diseases
Transplant success
Different types of transplant rejection classified according to time
Hyperacute
Acute
Chronic
how does Hyperacute graft rejection occure
Immediately due to preexisting antibody to the antigens on teh graft
Commonality of hyperacute graft rejection
rare
How does Acute GRaft rejection occure
Cell-mediated response against unmatched HLA antigens
When does Chronic Graft rejection occur
Months or years
what is the cause of Chronic GRaft rejection
Inflammatory damage to endothelial cells of vessels due to a weak cell-mediated reaction against minor HLA antigens
what is the result of Hyperacute rejection
Complement activation
endothetlial damage
Inflammation
thrombosis
what is the result of an acute rejection
Parenchymal cell damage
Interstitial inflammation
Endothelialitis
what is the result of ionchronic rejection
Chronic DTH reaction in vessel wall
Intimal smooth msucle cell proliferation
Vessel occlusion
who is at risk for Graft-Versus-Host (GVH) Disease
Immunocompromised individuals (not a problem in Immunocompetent people)
what are the T cells capable of in grafts
They are mature and capable of cell-mediated destruction of tissues in the recipient
What are Transfusion reactions
Antibodies agisnt blood group antigens
how are a and B blood antigens expressed
Codominant
what antibodies do people have in response to a or B blood type
antigens to antibodies to whatever they lack
how are anti-a and anti b antibodies produce
Made by similar antigens on naturally occuring bacteria in the intestinal tract
what class are antibodies for A and B blood type
IgM
Universal donor
O blood type
Universal acceptor
AB blood typ
history of Immunodeficiency discription
Hippocrates: 400 bc Da Vinci: 1510 AD Traygdon Wilsmyth: 1770 Louis PAstuer: 1880 Ogden Bruton: 1950
what was the first primary immunodeficiency disease to be described
Bruton Agammaglobulinemia
What did Colonel Ogden Bruton note
1952, absence of Immunoglobulins in a boy with a history of pneumonias and other bacterial infections
First physican to provide specific immunotherapy for X linked disorder by administering intramuscular injections of IgG
Types of Immunodeficiencies
PRimary/Congenital Immunodeficiencies
Secondary/acquired immunodeficiencies
What are Primary/Congenital immunodeficiencies
Genetic defects that result in an increased susceptibility to infection
when do Primary/COngenital Immunodeficiences manifest
In infancy and Childhood
How many people have Primary or congenital immunodeficiencies
1:500 in the US
what do Secondary or acquired Immunodeficiencies develop as
As a consequence of: Malnutrition Disseminated Cancer Treatment with immunosuppressive drugs Infection of cells of the immune system
how common are Toll-Like receptors
Conserved across widely diverse species
What can Primary immunodeficiency disorders affect
one+ components of the immune system
T, B lymphocytes, NK cells, Phagocytic cells and complement proteins
Immunodeficiencies from Primary Immunodiciencies may result from what
Defects in leukocyte maturation, activation from defects in effector mechansisms of innate and adaptive immuntiy
what is the principle consequence of an immuno-deficiency
INcreased susceptibility to infection
What determines the nature of the infection due to an immunodeficiency
Depends on the componenent of the immune system that is defective
Deficient humoral immunity results in
Increased susceptibility to infection by pyogenic bacteria
other name for X-linked Agammaglobulinemia(XLA)
Bruton’s Agammaglobulinemia
What is XLA
All antibody isotypes are very low (not even IgM or IgD)
Circulating B cells are absent
PRe-B cells are present in reduced numbers in bone marrow
What happens to the tonsils and lymph nodes due to XLA
Tonsils are usualy very small
Lmph nodes rarely palpable due to lack of gerinal center
Thymus changes due to XLA
Architecture is normal b/c t-cell dependent areas of spleen and lymph nodes
Why do boys with XLA remain healthy for the first 6-9 months of life
Maternally transmitted IgG antibodies
What happens after a while for guys with XLA
Get a lot of extracellular pyogenic organisms infections
What is the defect due to XLA
Loss of function of Bruton Tyrosine Kinase
Roll of Bruton Tyrosine Kinase
Pre-B cell expansion and maturatio into Ig-expressing B cells
What characterizes X-linked immunodeficiency with Hyper-IgM
Low serum IgG, IgA, and IgE
High levels of polyclonal IgM
When do patients with Hyper-IgM become symptomatic
after the 1st or second year of life with recurrent pathogenic infections
How are patients with XLA different than that of Hyper-IgM
Hyper IgM patients have lymphoid hyperplasia
What is the defect in X-linked immunodeficiency with hyper-IgM
Loss of CD40 ligand (CD154) that is expressed on helper T cells
What does Loss of CD40 ligand (CD154) lead to
Prevents the T cell from co-stimulating antigen-specific B cells (through CD40)
B cells are not signalted be the T cell to go through isotype sqitching and only produce IgM
How to treat immunodeficiencies for humoral immune response
Routine – prophylactic antibiotics and/or gamma-globulin therapy
What results in increased susceptibility to viruses and other intracellular pathogens
Deficient Cell-mediated Immunity
How to treat defects associated with deficient T cell responses
It is very hard to treat
How long can people live with Defects in T-cell function
Not long, rarely past infancy or childhood
Commonality of X-linked Recessive Severe Combined Immunodeficiency disease
Rare
What is a Severe combined Immunodeficiency
A rare, fetal syndrome characterized by profound deficiencies of T- and B-cell function
what is the most common form of Severe combined Immunodeficiency(SCID)
X linked SCID(XLSCID)
When do people present XLSCID
Within the first few months of Life
Symtpoms of XSCID in early life
Diarrhea, pneumonia, otitis, sepsis, cutaneous infections
growth of someone with XLSCID
may be normal initially, but extreme wasting usually develops after infections and diarrhea begins
What do people with XLSCID often have
Persistent infections due to opportuistic organisms (candida albicans, pneumocysits carinii, varicella, measles, parainfluenzae, cytomegalovirus, ebv)
Can infants with XLSCID get grafts
Lack the ability to reject foreign tissue and therefore are at risk for GCHD
when can GVHD ocure in XLSCID
when maternal T cells cross into fetal circulation while the SCID infant is in utero
What cells do XSCID patients lack
They have few or no T cells and NK cells
What cells do XSCID patients have a lot of
B cells ( don’t produce immunoglobulin normally, even after T cell reconstitution by bone marrow transplantation)
what are the aims of current treatments for Immunodeficienceies
- Minimize and control infections
2. replace the defective or absent components of the immune system by adoptive transfer and or transplantation
What is valuable for agammaglobulinemic parients to save their lives
Passive immunization with pooled gamma globulin
what is the treatment of choice for various immunodeficiency disease
Bone marrow transplantation
Successfulness of Bonemarrow transplantation
it can treat SCID and other similar diseases
Short lived Cellular reservoir of HIV
CD4+ T cells for the first phase of decay with a half life of 1 day
Productively infection long lived cells for HIV
Monocytes and macrophages for the second phase of decay with a half life of 2 weeks
Productively infected resting memory cells for HIC
Resting/memory CD4+ cells as the 3rd phase of decay greater than 50 years
Progression of HIV
Primary infection of cells in blood, mucosa
Infection established in lymphoid tissues (lymph node)
Acute HIV syndrome, spread of infection throughout the body
Immune response
Clinical latency
AIDS
Acute HIV syndrome with spread of infectionthroughout the body
Viremia
Immue response to HIV effectiveness
PArtial control of viral replication
What happens during the Clincial latency of HIV
Estblishment of Chronic infection
Virus trapped in lymphoid tissues by folicular dendric cells
low level viral production
then more microbial infections leads to increased viral replicaion
what happens with AIDS
Destruction of Lymphoid tissues
Depletion of CD4+ T cells
