Summary About 10–15% of patients with multiple sclerosis (MS) present with gradually increasing neurological disability, a disorder known as primary-progressive multiple sclerosis (PPMS). Compared with relapse-onset multiple sclerosis, people with PPMS are older at onset and a higher proportion are men. Inflammatory white-matter lesions are less evident but diffuse axonal loss and microglial activation are seen in healthy-looking white matter, in addition to cortical demyelination, and quantitative MRI shows atrophy and intrinsic abnormalities in the grey matter and the white matter. Spinal cord atrophy corresponds to the usual clinical presentation of progressive spastic paraplegia. Although neuroaxonal degeneration seems to underlie PPMS, the pathogenesis and the extent to which immune-mediated mechanisms operate is unclear. MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective. Future research should focus on the clarification of the mechanisms of axonal loss, improvements to the design of clinical trials, and the development of effective neuroprotective treatments.

Primary-progressive multiple sclerosis

In patients with primary and secondary progressive multiple sclerosis (MS), major differences in the pattern and extent of abnormality on cerebral magnetic resonance imaging (MRI) between the two groups have recently been demonstrated. In the present study, 24 patients, matched for age, sex, duration of disease, and disability, had serial gadolinium diethylenetriaminepentaacetic acid-enhanced MRI over a 6-month period. The 12 patients in the secondary progressive group had a total of 109 new lesions over this time (18.2 lesions per patient per year) and 87% of these enhanced. Enhancement also occurred within and at the edge of preexisting lesions. In contrast, only 20 new lesions were seen in the primary progressive group (3.3 lesions per patient per year) and only one of these enhanced. There was no difference in the degree of clinical deterioration between the two groups over the 6-month period. These findings may indicate a difference in the dynamics of disease activity between the two forms of progressive MS, particularly in relation to the inflammatory component of the lesions, and have important implications for the selection of patients and the monitoring of disease activity in therapeutic trials.

Major differences in the dynamics of primary and secondary progressive multiple sclerosis.

Multiple sclerosis (MS) has, since the 1970s, been known to be associated with the HLA-Dw2 and -DR2 specificities in Caucasian Europeans and North Americans. By the use of genomic typing techniques, the association has been specified to be with the DRw15,DQw6,Dw2, i.e. the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. A significant DPw4 association in Scandinavian MS patients has been described in one report. However, this association has not been confirmed in several subsequent studies with patients from the same and other ethnic groups. During the last few years several reports, based on serological, RFLP and PCR-SSO data, have suggested that the HLA class II-associated MS susceptibility gene(s) may be more closely associated with the DQ than with the DR subregion. The observations that the HLA-DQB1 genes of MS patients share long stretches of sequence motifs and also carry DQA1 alleles encoding glutamine at position 34 of the DQ alpha chain have received considerable attention. It has been suggested that the susceptibility to develop MS might be determined by the corresponding DQ alpha-beta heterodimers either encoded in cis or in trans. We have investigated these issues in a large group of Swedish MS patients (n = 179). We found that the associations with the suggested DQB1 sequences and position 34 of the DQ alpha chain were due to linkage disequilibrium and secondary to the association with the DRw15,DQw6,Dw2 haplotype (p less than 10(-9) and p less than 10(-8), respectively). No overrepresentation of the implicated DQ alpha-beta heterodimers was observed in DRw15,DQw6,Dw2-negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hla class ii-associated genetic susceptibility in multiple sclerosis : a critical evaluation

The worldwide distribution of multiple sclerosis (MS) can be described within three zones of frequency: high, medium, and low. The disease has a predilection for white races and for women. Migration studies show that changing residence changes MS risk. Studies of persons moving from high- to low-risk areas indicate that in the high-risk areas, MS is acquired by about age 15. Moves from low- to high-risk areas suggest that susceptibility is limited to persons between about ages 11 and 45. MS on the Faroe Islands has occurred as four successive epidemics beginning in 1943. The disease appears to have been introduced by British troops who occupied the islands for 5 years from 1940, and it has remained geographically localized within the Faroes for half a century. What was introduced must have been an infection, called the primary MS affection (PMSA), that was spread to and from successive cohorts of Faroese. In this concept, PMSA is a single widespread systemic infectious disease (perhaps asymptomatic) that only seldom leads to clinical neurologic MS. PMSA is also characterized by a need for prolonged exposure, limited age of susceptibility, and prolonged incubation. I believe that clinical MS is the rare late outcome of a specific, but unknown, infectious disease of adolescence and young adulthood and that this infection could well be caused by a thus-far-unidentified (retro)virus. Images

Epidemiologic evidence for multiple sclerosis as an infection.

HLA class II gene polymorphism was investigated in 100 patients with clinically definite multiple sclerosis (MS) by restriction fragment length polymorphism analysis of Taq I-digested DNA using DRB, DQA, and DQB cDNA probes. Twenty-six patients had primarily chronic progressive MS and 74 had relapsing/remitting MS. The latter group included patients with a secondary progressive evolution of symptoms. Both clinical forms of MS were found to be associated with the DRw15,DQw6 haplotype. In addition, primarily chronic progressive MS was positively associated with the DQB1 restriction fragment pattern seen in DR4,DQw8, DR7,DQw9, and DRw8, DQw4 haplotypes, as well as negatively associated with the Taq I DQB1 allelic pattern corresponding to the serological specificity DQw7. Relapsing/remitting MS was positively associated with the DQB1 allelic pattern observed in the DRw17,DQw2 haplotype. These three DQB1 alleles are in strong negative linkage disequilibria with DRw15. The two susceptibility markers of each clinical form of MS act additively in determining the genetic susceptibility, as the relative risks for individuals carrying both markers roughly equal the sum of respective risks. Different alleles of the DQB1 locus defined by restriction fragment length polymorphisms contribute to susceptibility and resistance to primarily chronic progressive MS as well as to susceptibility to relapsing/remitting MS. The observed immunogenetic heterogeneity between the different clinical forms of MS favors the hypothesis that primarily chronic progressive MS and relapsing/remitting MS are two distinct disease entities.

Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities.

This study reports the frequencies of HLA antigens and the polymorphic variants of C4, C2, and Bf for 200 patients with multiple sclerosis (MS) living in the Grampian region of Scotland, an area of high disease prevalence. A group of 128 normal subjects from the same region were typed for comparison. Although the frequencies of HLA-B7 and DR2 in the patient group (43.3% and 49.4%, respectively) were found to be similar to those reported for other Northern European HLA studies on patients with MS, high frequencies of these antigens were also observed in the group of normal Grampian subjects (38.3% and 40.6%) the differences were not statistically significant. However, a significant association was found between the recently defined Class II HLA antigen, DQw1, and MS (P less than 0.006) when compared with controls. There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf when the group of patients with MS was compared with the control group of normal subjects. The patients were subdivided according to disease severity, remittent versus progressive clinical course, age of onset of the disease and initial symptoms. The frequencies of the HLA and complement polymorphisms (C4, C2, and Bf) were analysed in these subdivisions. DQw1 was found with similar frequency in severe and benign disease (78% and 80%, respectively) but DR2 was most frequent in the group of patients with remittent disease (54%). There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf between the above subgroups of patients and overall no significant HLA associations were found with age of onset of disease or initial symptoms. The findings suggest that in an area of high prevalence of MS, the disease is more closely associated with DQw1 than DR2. Furthermore, there was no evidence to support the hypothesis that the HLA region complement gene polymorphisms show significant association with a putative HLA-linked MS susceptibility gene.

Multiple sclerosis in north-east scotland an association with hla-dow1

Fourteen multiplex MS families, 9 single-case MS families and 11 normal families from the Grampian region of North-East Scotland were studied. The prevalence rate of MS for individuals in multiplex families was calculated at 809/100,000; 4.5 times the prevalence rate for the general population in this region. The distribution of shared haplotypes in 12 affected and 19 unaffected sib-pair comparisons did not differ significantly from that expected by chance. Furthermore there was no evidence that homozygosity of a particular HLA gene was required for increased susceptibility to the disease. HLA-B7, C4A3, C4B1, BfS, HLA-DR2, HLA-DQw1 was the commonest haplotype accounting for 18.9% and 24.2% of parental haplotypes from multiplex and single-case families, respectively, compared with 2.3% of parental haplotypes from control families (p less than 0.05 and p less than 0.01, respectively). No significant differences were observed in the frequencies of complement gene polymorphisms (Factor B and C4). The data suggests that a MS susceptibility gene exists, in the HLA complex, and is in closest linkage disequilibrium with the HLA-D region; although other factors, environmental and/or independent genetic loci, may have an important influence.

HLA genetic determinants in familial MS. A study from the Grampian region of Scotland.

The well known HLA/disease associations have often in the past been attributed to the effects of Class 1 or 11 MHC products on an individual’s immune responsiveness. However there are reasons for thinking that more than one mechanism may be responsible for these associations. In this paper, we will outline the evidence which leads us to conclude that the Class 111 genes, encoding polymorphisms for the complement system proteins of C4A, C4B, and C2 govern susceptibility to systemic lupus erythematosus (SLE).

https://link.springer.com/content/pdf/10.1007%2F978-1-4612-5014-2_23.pdf

Class III HLA Genes and Systemic Lupus Erythematosus

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Multiple sclerosis in north-east scotland an association with hla-dow1

HLA genetic determinants in familial MS. A study from the Grampian region of Scotland.

Class III HLA Genes and Systemic Lupus Erythematosus