nonresponders, MBP, alleles: a miscellany

[Guest guest]

An early morning miscellany, not thorough, but illustrating the effect that MHC

alleles can have.

One of the great mysteries of the last millenium is why the NIH and its

subsidiary corporations ignore (a) the findings of Warren et al, and (

the significance of those findings.

HepB (1), diptheria (2), MBP (3), autism (4).

1. Hum Immunol 1998 Apr;59(4):212-8

The influence of major histocompatibility complex class II genes

and T-cell Vbeta repertoire on response to immunization with HBsAg.

Hohler T et al.

Nonresponsiveness to HBsAg vaccination is observed in 5-10% of vaccine

recipients and is possibly

caused by a defect in the T helper cell compartment. The immune response to

HBsAg is influenced by

genes of the major histocompatibility complex. We have investigated MHC class I

and class II antigens in

53 adult responders and 73 nonresponders. Results obtained in this first study

were tested in a second

study with 56 responders and 62 nonresponders from an infant vaccination trial.

In addition, the

peripheral Vbeta-chain T-cell receptor repertoire was investigated using

monoclonal antibodies and

flow-cytometry in 26 adult responders and 38 nonresponders. As previously

reported, nonresponsiveness

to HBsAg vaccination was associated with DRB1*3 and DRB1*7. In addition, DRB1*13

was

significantly increased among vaccine responders (35.2% vs 5.4%;p < 0.0001)

suggesting an immune

response promoting effect for this allele whereas the closely related allele

DRB1*14 was associated with

nonresponse in the infant study. There was no evidence for a hole in the T cell

receptor Vbeta repertoire.

In conclusion, in agreement with results obtained in mice there appears to be a

hierarchy of DRB1*

genes in the HBsAg immune response. The possible differential association of

DRB1*13 and DRB1*14

may allow the identification of differences between responsiveness and

nonresponsiveness to a few

amino acid differences in the beta1-domain of the class II heterodimer.

2. J Immunol 1992 May 1;148(9):2703-8

Mutations in the third, but not the first or second, hypervariable regions of

DR(beta 1*0101) eliminate DR1-restricted recognition of a pertussis toxin

peptide.

Olson RR, De Magistris MT, Di Tommaso A, Karr RW

Department of Veterans Affairs Medical Center, Iowa City, IA.

We have examined the role of 12 polymorphic residues of the beta-chain of the

HLA-DR1 class II

molecule in T cell recognition of an epitope of pertussis toxin. Murine L cell

transfectants expressing

wild-type or mutant DR1 molecules (containing single amino acid substitutions in

DR(beta 1*0101))

were used as APC in proliferation assays involving nine DR1-restricted T cell

clones specific for peptide

30-42 of pertussis toxin. Four different patterns of recognition of the mutants

were found among the

pertussis-specific clones. Residues in the third hypervariable region (HVR) of

DR(beta 1*0101) are

critically important for all the T cell clones; amino acid substitutions at

positions 70 and 74 abrogated

recognition by all of the T cell clones, and substitutions at positions 67 and

71 eliminated recognition by

most of the clones. In contrast, most single amino acid substitutions in the

first and second HVR,

predicted to be located in the floor of the peptide binding groove, had little

or no effect on the

proliferative responses of these clones. However, the involvement of beta-chain

first and second HVR

residues was demonstrated by the inability of transfectants expressing wild-type

DR(beta 1*0404)

(DR4Dw14) or DR(beta 1*1402) (DR6Dw16) to present peptide to these clones. These

beta-chains have

completely different first and second HVR compared with DR(alpha,beta 1*0101)

although the third HVR

are identical. These results illustrate the functional importance of third HVR

residues of DR(beta 1*0101)

and allow definition of the molecular interactions of the DR1 molecule with the

30-42 peptide.

3. Nat Genet 1999 Nov;23(3):343-7

A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell

receptor.

Madsen LS et al.

Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected

autoimmune

pathogenesis. Although there is evidence that the development of MS is

determined by both

environmental influences and genes, these factors are largely undefined, except

for major

histocompatibility (MHC) genes. Linkage analyses and association studies have

shown that susceptibility

to MS is associated with genes in the human histocompatibility leukocyte

antigens (HLA) class II region,

but the contribution of these genes to MS disease development less compared with

their contribution to

disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage

disequilibrium in the

MHC class II region, it has not been possible to determine which gene(s) is

responsible for the genetic

predisposition. In transgenic mice, we have expressed three human components

involved in T-cell

recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule:

DRA*0101/DRB1*1501

(HLA-DR2), an MHC class II candidate MS susceptibility genes found in

individuals of European

descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone

specific for the HLA-DR2

bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4

coreceptor. The

amino acid sequence of the MBP 84-102 peptide is the same in both human and

mouse MBP. Following

administration of the MBP peptide, together with adjuvant and pertussis toxin,

transgenic mice developed

focal CNS inflammation and demyelination that led to clinical manifestations and

disease courses

resembling those seen in MS. Spontaneous disease was observed in 4% of mice.

When DR2 and TCR

double-transgenic mice were backcrossed twice to Rag2 (for

recombination-activating gene 2)-deficient

mice, the incidence of spontaneous disease increased, demonstrating that T cells

specific for the

HLA-DR2 bound MBP peptide are sufficient and necessary for development of

disease. Our study

provides evidence that HLA-DR2 can mediate both induced and spontaneous disease

resembling MS by

presenting an MBP self-peptide to T cells.

4. J Neuroimmunol 1996 Jul;67(2):97-102

Strong association of the third hypervariable region of HLA-DR beta 1 with

autism.

Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, s WW, AR

We reported that the major histocompatibility complex (MHC) including the null

allele of the C4B gene

and the extended haplotype B44-C30-DR4 is associated with autism. We report now

that the third

hypervariable region (HVR-3) of certain DR beta 1 alleles have very strong

association with autism. The

HVR-3 of DR beta 1* 0401 or the shared HVR-3 alleles DR beta 1* 0404 and DR beta

1* 0404 and DR

*0101, was expressed on extended haplotypes in 23 of 50 (46%) autistic subjects

as compared to only 6

of 79 (7.5%) normal subjects. Another HVR-3 sequence, the DR beta 1* 0701

allele, was carried on

extended haplotypes in 16 (32.0%) of the autistic subjects as compared to 8

(10.1%) of the normal

subjects.