Immunodeficiencies

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Immunodeficiencies

• Primary
• Usually result from one or more mistakes during
  lymphocyte development
• Acquired
• Alteration of an existing immune system
• AIDS (acquired immunodeficiency syndrome)

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Cancers during stages of lymphocyte development
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Lymphocyte Development

• Where can things go wrong?
• Stem cell replication and differentiation

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Lymphocyte Development

• Where can things go wrong?
• Stem cell replication and differentiation
• B-lymphocyte differentiation

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Somatic recombinationsCell replications
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Lymphocyte Development

• Where can things go wrong?
• Stem cell replication and differentiation
• B-lymphocyte differentiation
• T-lymphocyte differentiation

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• Somatic Recombinations
• Cell replications

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Positive Selection
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X-linked agammaglobulenemia

• Sex-linked (X chromosome)
• Inherited (primary) immunodeficiency
• Btk (Brutons tyrosine kinase) deficiency

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X-linked agammaglobulenemia

• Sex-linked (X chromosome)
• Inherited immunodeficiency
• Btk (Brutons tyrosine kinase) deficiency
• Reaches pre-B cell receptor stage

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Severe Combined Immunodeficiencies

• Will affect BOTH B-cell and T-cell responses
• Dysfunctional RAG genes

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Severe Combined Immunodeficiencies

• Will affect BOTH B-cell and T-cell responses
• Dysfunctional RAG genes
• Somatic recombination events never get started
• Essentially NO functional B or T cells
• Adenosine deaminase deficiency
• ADA enzyme NOT produced
• Toxic by-products not broken down
• T-cells are most affected
• T-helper cell deficiency also affects B-cell
  responses

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ADA deficiency gene therapy

• Functional ADA gene inserted into lymphocytes
  using a virus vector
• Early results were promising
• ADA produced
• T-lymphocyte population increased
• Immune responses started
• Long-term prognosis is NOT good (yet)

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Bare lymphocyte syndrome

• Dysfunctional MHC Class II peptide presentation
• No T-helper cell development

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Positive Selection
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Bare lymphocyte syndrome

• Dysfunctional MHC Class II peptide presentation
• No T-helper cell development
• No T-helper cell mediated responses

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Bare lymphocyte syndrome

• Dysfunctional MHC Class II peptide presentation
• Dysfunctional TAP

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Bare lymphocyte syndrome

• Dysfunctional MHC Class II peptide presentation
• Dysfunctional TAP
• No initiation of T-cytotoxic cell responses

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Acquired Immunodeficiency Syndrome (AIDS)

• Caused by a virus (human immunodeficiency virus
  HIV)

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Acquired Immunodeficiency Syndrome (AIDS)

• Caused by a virus (human immunodeficiency virus
  HIV)
• HIV preferentially infects T-helper cells
• HIV Attaches to CD4 and to CCR5 (a chemokine
  receptor)

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• GP120 binds to CD4, then to CCR5

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Complete HIV infection cycle
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The results

• Infected T-helper cell is destroyed
• Released HIV then infect other T-helper cells

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The results

• Infected T-helper cell is destroyed
• T-helper cell sends a kill me signal using MHC
  Class I presented HIV peptides
• T-cytotoxic cells destroy virus-infected T-helper
  cells

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Chronic depletion of CD4 T-helper cells
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What to do about HIV/AIDS?

• Use drugs that interfere with one or more of the
  stages of HIV infection, replication, release.

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Use the immune system

• Antibodies to prevent HIV attachment

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Use the immune system

• Antibodies to prevent HIV attachment
• Specific for gp120 (or some portion)

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Use the immune system

• Antibodies to prevent HIV attachment
• T-cytotoxic cell destruction of HIV-infected
  cells before viral replication and release

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Use the immune system

• Expand HIV-peptide specific T-cytotoxic cell
  population before HIV infection
• MHC Class I presentation of HIV-peptide by
  non-infected cells without causing any harm
• Hey, what about using the dendritic cell to
  present the HIV peptides?
• Would prime AND expand the T-cytotoxic cell
  population
• DCs can also do cross-presentation
• What form of the vaccine material will be
  correctly processed and presented by the DC
  gp120?, other viral peptide?
• How about genetically manipulating the DC to
  express MHC Class I HIV peptides? insert HIV
  nucleotide sequence and necessary enzymes

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A solution for primary immunodeficiencies?

• Bone Marrow Transplant
• Why?
• Bone marrow is essentially a complete immune
  system

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A solution?

• Bone Marrow Transplant
• Why?
• Bone marrow is essentially a complete immune
  system
• Including fully mature B-cells and T-cells

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Uses of Bone Marrow Transplants

• Bone Marrow transplants used to replace
  non-existent, destroyed or non-functioning immune
  system
• Immunodeficiency diseases
• No immune system
• Cancers (when irradiation and chemotherapy are
  used to kill cancer cells)
• Immune system cells are very sensitive to these
  treatments (destroys immune system)

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Bone Marrow transplants

• Outcome is defined by MHC compatability
• IF there are any differences between MHCs in
  donor and recipient
• Recipient will treat foreign MHCs as non-self
  antigens
• Donor BM cells will be destroyed (rejected)

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Bone Marrow transplants

• Outcome is defined by MHC compatability
• IF there are any differences between MHCs in
  donor and recipient
• Recipient will treat foreign MHCs as non-self
  antigens
• Donor BM cells will be destroyed (rejected)
• Result is no effective replacement of immune
  system

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Bone Marrow transplants

• IF there are any differences between MHCs in
  donor and recipient AND the recipients immune
  system has been destroyed
• Donor lymphocytes will consider the foreign
  MHCs in the recipient as non-self and will begin
  to destroy entire recipient called a
  Graft-vs-Host response

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Bone Marrow transplants

• Ideal condition NO differences between MHCs in
  donor and recipient
• How might that condition be obtained?
• Autologous BM transplant
• Donor and recipient are the same person
• Only if cancer is not in the bone marrow

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Bone Marrow transplants

• Ideal condition NO differences between MHCs in
  donor and recipient
• How might that condition be obtained?
• Autologous BM transplant
• Syngeneic BM transplant
• Identical twin
• Sibling (25 chance of matching MHCs)

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Bone Marrow transplants

• Ideal condition NO differences between MHCs in
  donor and recipient
• How might that condition be obtained?
• Autologous BM transplant
• Syngeneic BM transplant
• Allogeneic BM transplant
• Donor recipient are NOT matched

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Bone Marrow transplants

• Ideal condition NO differences between MHCs in
  donor and recipient
• How might that condition be obtained?
• Autologous BM transplant
• Syngeneic BM transplant
• Allogeneic BM transplant
• Donor recipient are NOT matched
• Immunosuppressive drugs
• Recipient very susceptible to infections, cancers
• Graft-vs-host response may occur

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Allogeneic BM transplant - what to do?

• Try to find the perfect MHC match
• Chances are 1 in 20,000 (or higher)
• Community bone marrow drives
• Chance of finding the perfect match is slim
• Number of persons participating is too low

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Solution

• Expand the number of potential donors
• National Marrow Donor Program
• Volunteer to have your tissue typed
• Determines your set of MHCs
• Worldwide data bank of tissue types
• Can be searched for a compatible donor
• Donor contacted to see if willing to donate
• Outcome can be lifesaving

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Drive for Diversity
RITs Physician Assistant Class of 2011

• Wednesday, November 5
• 10 am 2 pm
• Clark Gym

2nd annual Marrow Registry Drive in honor of
Nicole Nelson, a PA from New Hampshire whose
Native American background made finding a match
very difficult. (A match was eventually made
with two donor cords from Australia!) Although
there are 7 million donors on the registry, each
day 6,000 people are still actively seeking a
match. Diversity is the most important measure
of a successful registry.
Saving a life is a 30 second mouth swab away
For more information, please visit
http//www.marrow.org/DONOR/When_You_re_Asked_to_D
onate_fo/Donation_FAQs/index.html or e-mail us
at ritmarrowdrive_at_yahoo.com