Download Major Histocompatibility Complex Class I Deficiency

Mystery Case
Kari C. Nadeau, MD, PhD
Stanford Immunodeficiency Case
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Case
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HPI
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17 yo female and 7 yo male with bronchiectasis from
Nevada
The 7 yo male had initial symptoms at 4 yo
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Recurrent sinopulmonary infections
+ HiB and S pneumo sputum cultures
Deny consanguinuity
PMx: Unremarkable
Received all vaccines without difficulties
FH
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3 healthy siblings
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Labs
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High IgG (1,784)
WBC of 4.3 K (rest of CBC normal)
Lymph phenotypes (repeated 3 occasions with similar results)
 86% CD3
 90% CD4
 10% CD8
 10% CD19
 4% CD16
High IgG titers to herpes, CMV, mumps, chicken pox, measles
Low IgG to influenza and EBV
CH50 normal
DHR normal
Mitogen and Antigen Assays normal
Normal DTH
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Labs
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Flow for MHC (post PBMC activation with
IFN-gamma)
Normal MHC II expression
 < 1% of normal MHC I production on cell
surface
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HLA typing
Inherited identical MHC haplotype from both
parents
 Other children were heterozygous
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To the bench
Normal MHC I mRNA expression
 Sequencing of TAP1 and TAP2 showed
homozygous nonsense mutation in TAP1
(peptide transporter system into ER for
MHC Class I attachment)
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Features seen in MHC 1 deficiency
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Autosomal recessive
Bronchiectasis
Pansinusitis
Pneumonia (H. infl., Pseudo, S. pneumo,
Klebsiella, E coli, Staph aureus)
Nasal polyposis
Severe cutaneous necrotizing granulomas
leading to ulceration and organ involvement
(skin and lung)—about 50% and mostly in adults
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No organisms cultured
Unresponsive to antibiotics
Unresponsive to immunosuppression
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Question 1
Why were the CD8 T cell numbers decreased
while CD4 numbers remained normal?
No thymic presentation of MHC I molecules to T
cells, so no opportunity to positively select for
CD8+ T cells.
Note: Some cases present with normal T subsets
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Cell-mediated and humoral
immunity in MHC 1 deficiency
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Over 22 patients reported in literature since
Tourraine et al. 1978
3 groups: Group I (severe, with TAP defect),
Group 2 (asymptomatic with TAP defect) and
Group 3 (atypical with unknown genetic etiology)
Immune tests:
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Normal T cell numbers in 2, slow decrease in all T
cells in 1, plus these 2 patients
LFAs to mitogens normal in 2 of 3 patients.
LFAs to antigens normal in 2 of 2 patients
DTH skin test normal in 3 tested
1 with low IgM, 1 with low IgG2 and IgG4
Normal antibody responses in all tested
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So why immunodeficiency?
NK cells appear overactive (increased
cytotoxicity to autologous cells)
 Hypothesis
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Patients’ cells can not upregulate MHC1
expression in response to IFN gamma which
would protect from NK cell cytotoxicity
 Increased NK cell activity lead to auto-toxicity
and tissue destruction
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Why do TAP defects lead to no
MHC 1 complex expression?
MHC 1 complex is unstable without bound
peptide (polymorphic HLA A,B,C
associated with Beta 2 microglobulin) and
is rapidly degraded in ER
 Without bound peptide, MHC 1 complex
does not get transported from ER to cell
surface
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Question 2
TCRs on CD8+ T cells in these children
were all gamma:delta (no alpha:beta).
Why is this?
Maturation of gamma:delta T cells is
independent of MHCs because they
recognize antigen independently of the
MHC. Therefore, the development of
these T cells was not affected.
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Question 3
These children had normal DTH. Why is
this?
DTH is mediated by CD4+ T cells
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Question 4
Why did these children have high IgG levels?
Immunoglobulin production by B cells is driven by
cytokines derived from CD4+ cells and inhibited
by cytokines derived from CD8+ cells. Without
CD8+ cells, the inhibitory signals were lost.
Note: Some patients present with normal IgG
levels
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Not quite that straightforward
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Question 5
TAP 2 defects have also been found. How
would these children present?
Same as TAP1 defects since both proteins
are equally important for transport into ER
(Note: TAP1 homodimers can transport
some peptides)
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Therapy is symptomatic
Antibiotics as needed
 Topical therapy for skin ulcers
 Chest physiotherapy
 Gene Tx—difficult b/c of ubiquitous nature
of Class I
 Transplant-difficult b/c of high risk of
GVHD with NK cells
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Overall
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Clinical and biological heterogeneity
Tight control of infections
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MHC Background
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Major Histocompatibility
Complexes
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What is a MHC?
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A family of protein complexes present on
almost all cell types
What do the MHCs do?
Bind peptide fragments derived from
pathogens and display them on the cell
surface for recognition by T cells
 The marker of “self”
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MHC Types (chromo 6)
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Class I
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Class II
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Present on all cells (almost)
Recognized by CD8+ T cells
HLA-A, HLA-B, HLA-C…
Present on antigen presenting cells
Recognized by CD4+ T cells
HLA-DP, HLA-DQ, HLA-DR…
Class III
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Genes present in MHC regions of chromosome 6 that
encode complement proteins (C4, C2, factor B), TNF,
and other immune related proteins.
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MHC Features
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Polygenic
>200 MHC genes on three different
chromosomes
 Leads to wide variety of MHCs in the
population
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Highly polymorphic
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Even individuals with “same” MHC have
MHCs transcribed from numerous variant
alleles
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Consequences of polygenic and
highly polymorphic MHC
Pathogens can’t reasonably evade the
huge number MHC polymorphisms found
in non-isolated populations
 Each polymorphism presents a different
peptide product from a pathogen
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Each individual will have different
susceptibility to a given pathogen, so…
 Epidemic spread of a particular pathogen is
quite difficult
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MHC Inheritance
MHCs are co-dominant
 There are 3 main MHC I genes (HLA-A,
HLA-B, HLA-C), so each individual
expresses 6 MHC I genes (1 set from
each parent).
 Similarly, there are 3 main MHC II genes,
so each individual expresses 6 MHC II
genes
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MHC Genes
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MHC Class I Specifics
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MHC Class 1
Infected cells present pathogen derived
peptides on MHC class 1 molecules
 MHC class 1 molecule plus antigen
recognized by antigen-specific CD8+ T
cell
 Cell killing initiated by CD8+ T cell
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MHC I production and loading
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Proteosome
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MHC1 molecule
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MHC 1 molecule
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CD8 molecule
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MHC1 and peptide binding
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MHC1 CD8 Interactions
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CD8+ mediated cytotoxicity
Perforin
 Granzymes
 TNF
 Fas ligand
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Perforin
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Fas:Fas ligand pathway
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Thank you
Zimmer, et al. Q.J. Med. 2005
Gadola, S.D., et al. Clin Exp Immunol 2000
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Additional slides
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MHC class IB: MHC type
molecules
Genes encoding MHC Class I type
molecules
 Few polymorphisms
 Variable function and mechanisms of
action
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Mostly unknown
Somewhat similar to pattern recognition
receptors of innate immunity
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MHC class IB innate immunity-like
functions
Presentation of peptides (via H2-M3
molecules) with N-formylated amino
termini
 Expression of MIC gene products by
infected cells recognized by NK cells
 Expression of HLA-G on placental cells
recognized by NK cells
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Alloreactivity
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Some T cells (1-10% of T cell population)
can recognize MHCs of many different
polymorphisms
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The goal of thymic education is to develop T
cells that can react against foreign antigen, so
T cell receptors can intrinsically bind to a nonself MHC molecule as long as the “fit” is
reasonably close
Principal behind mixed lymphocyte
reaction
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Mechanism of alloreactivity
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