- Email: [email protected]
AGE RELATIONSHIP BETWEEN INSULIN-DEPENDENT DIABETES AND RARE ALLELES OF PROPERDIN FACTOR B
537 many indigenous strains of L. pneuwe can learn more about the antithat mophila possible this structure of group. genic The features we have described may prove helpful to those who are anxious to isolate more strains, especially the follow-
urgent need
to
collect
as
so
as
’
ing : on steroid therapy who die rapidly from pneumonia frequently infected with L. pneumophila than others. Both Cambridge isolations have been from such patients. (b) Patients who die within 8 days of the onset of pneumonia will have no antibody to L. pneumophila detectable by present methods. Many who die within 14 days will also have no detectable antibody.4 (c) Immunofluorescent staining of post-mortem lung smears with direct conjugates may be negative when the organism is of a different
(a) Patients
may be
more
serogroup
or a
variant such
as
the
describe. Indirect immunoother techniques5.6are worth but not for specific identification
one we
fluorescence, modified Gram staining,
or
consideration as a diagnostic guide of the strain. (d) The culture of dilutions of lung suspension is invaluable. (e) A morphologically typical isolate should not be discarded because of failure to stain with the range of sera now available. Public Health Laboratory Service, Addenbrooke’s Hospital,
Cambridge CB2 2QW
J. NAGINGTON T. G. WREGHITT D. J. SMITH
AGE RELATIONSHIP BETWEEN INSULIN-DEPENDENT DIABETES AND RARE ALLELES OF PROPERDIN FACTOR B
SiR,—The report by Raum and colleagues’ of a striking association between insulin-dependent diabetes (IDDM) and the rare genetic type Fl in the properdin factor B system has been confirmed independently in studies from our laboratories reported to a meeting of the Human Genetics Society of Australasia (Queenstown, New Zealand, June 27-29, 1979). Raum et al. found the Bf Fl factor in 22.6% of U.S. White IDDM patients compared with 1 - 9% of the general population, giving a relative risk of 15-0. In our study of 281 Australian IDDM patients 8.9% had the Fl factor compared with 2-1% in 380 controls, a relative risk of 4.5. Our study indicates also that there is a slight increase in the frequency of the other rare Bf factor, S 1, being 2-8% in patients and 1-1% in controls. Raum et al. also reported a similar increase in Sl :2 -4% v 1.0% The discrepant estimates of relative risk that people with the Fl factor will have IDDM may well reflect different age compositions of the two study populations, although Raum et al. did not provide age distributions for their U.S. patients. The frequency of Bf Fl is highly age-dependent (see accompanying figure). The Fl factor is present in 19.1% of 47 Australian IDDM patients aged 10 years or less, falling progressively to 1.3% in 79 patients over 20 years of age. If the frequency of the Bf Fl and Sl factors are combined we find a decline from 23.4% in the youngest to 2.5% in the oldest group, compared with 3.2% among controls. The relative risk for Bf Fl+ Sl1 is 9.4 in patients 10 years or younger. Age-dependent relative risks in IDDM have peviously been reported2 for HLA Bwl5. In our own series relevant HLA data are available for 148 of the IDDM patients. There is no significant difference in the frequency of B8 for patients in the various age categories, but for Bwl5, 14% (13/93) are in the 0-10 age’group and 9.3 (5/54) are in the 10-20 age group. The numbers are small but the trend is in the same direction as that
age to
frequency
of
rare
Bf factors in 281 Aus-
tralian IDDM patients.
The rapid decline in the frequency of Bf F1with increasing age of patients with IDDM is compatible with a viral stimulus for initiating the disease process. If Bf Fl is in positive linkage disequilibrium for a susceptibility allele then young children carrying the Fl allele are more likely not to resist an infection, with consequent development of autoimmune responses and islet-cell destruction. With increasing age the development of partial immunity in the child population may reduce the strength of the interaction between the precipitating agent and factors linked to the susceptibility allele. In our laboratories we have demonstrated also a high frequency of lymphocytotoxins (LCs) in sera of patients with IDDM. There is a strong association between the presence of LCs and HLA type: they were present in 37% of patients homozygous for either B8 or Bwl5 compared with 16% in those not homozygous for either. A similar relationship is present for LCs and Bf factors: they were present in 38% of patients with the Bf Fl factor compared with 17% in patients without this factor. Since in our data Bf Fl is in strong negative disequilibrium with HLA-B8,3 this relationship between LCs and Bf Fl is not due to the similar relationship between
LCs and HLA-B8. Islet-cell antibodies are also more frequent in sera of IDDM patients who are HLA-B8and this relationship is even stronger in those patients in whom islet-cell antibodies have persisted for 5 years or more. We are now investigating the relationship between the frequency of Fland Sland age of the patient, together with the ’significant association between Fl and the presence of lymphocytotoxins, suggest that Bf typing will be of increasing importance in differentiating various factors in the aetiology and progress of insulin-dependent diabetes. -
Human Biology Department, John Curtin School of Medical Research, Canberra, Australia
R. L. KIRK S. W. SERJEANTSON
JAYA THEOPHILUS P. ZIMMET S. WHITEHOUSE
Royal SouthernMemorialHospital,
of Dausset.1
Melbourne
5. de Freitas
JL, Borst J, Meenhorst PL. Easy visualisation of Legionella pneumophila by"halfa Gram" stain procedure. Lancet 1979; i: 270-71. 6. Rodgers FG. Staining of Legionella pneumophila. Lancet 1979; i: 551. 1. Raum D, Alper CA, Stern R, Gabbey KH. Genetic marker for insulin-dependent diabetes mellitus. Lancet 1979; i: 1208-09. 2. Dausset J. In: HLA and disease. Dausset J, Svejgaard A, eds. Copenhagen;
Munksgaard,
Relationship of
1977: 296.
Royal Children’sHospital,
J. M. COURT
Melbourne
3. Kirk
RL, Theophilus J, press). 4. Morris, PJ, Vaughan H,
Whitehouse S, Court
JM,
Zimmet P. Diabetes
(in
Irvine WJ, et al. HLA and pancreatic islet cell antibodies in diabetes. Lancer 1976; ii: 652-53.
urgent need
to
collect
as
so
as
’
ing : on steroid therapy who die rapidly from pneumonia frequently infected with L. pneumophila than others. Both Cambridge isolations have been from such patients. (b) Patients who die within 8 days of the onset of pneumonia will have no antibody to L. pneumophila detectable by present methods. Many who die within 14 days will also have no detectable antibody.4 (c) Immunofluorescent staining of post-mortem lung smears with direct conjugates may be negative when the organism is of a different
(a) Patients
may be
more
serogroup
or a
variant such
as
the
describe. Indirect immunoother techniques5.6are worth but not for specific identification
one we
fluorescence, modified Gram staining,
or
consideration as a diagnostic guide of the strain. (d) The culture of dilutions of lung suspension is invaluable. (e) A morphologically typical isolate should not be discarded because of failure to stain with the range of sera now available. Public Health Laboratory Service, Addenbrooke’s Hospital,
Cambridge CB2 2QW
J. NAGINGTON T. G. WREGHITT D. J. SMITH
AGE RELATIONSHIP BETWEEN INSULIN-DEPENDENT DIABETES AND RARE ALLELES OF PROPERDIN FACTOR B
SiR,—The report by Raum and colleagues’ of a striking association between insulin-dependent diabetes (IDDM) and the rare genetic type Fl in the properdin factor B system has been confirmed independently in studies from our laboratories reported to a meeting of the Human Genetics Society of Australasia (Queenstown, New Zealand, June 27-29, 1979). Raum et al. found the Bf Fl factor in 22.6% of U.S. White IDDM patients compared with 1 - 9% of the general population, giving a relative risk of 15-0. In our study of 281 Australian IDDM patients 8.9% had the Fl factor compared with 2-1% in 380 controls, a relative risk of 4.5. Our study indicates also that there is a slight increase in the frequency of the other rare Bf factor, S 1, being 2-8% in patients and 1-1% in controls. Raum et al. also reported a similar increase in Sl :2 -4% v 1.0% The discrepant estimates of relative risk that people with the Fl factor will have IDDM may well reflect different age compositions of the two study populations, although Raum et al. did not provide age distributions for their U.S. patients. The frequency of Bf Fl is highly age-dependent (see accompanying figure). The Fl factor is present in 19.1% of 47 Australian IDDM patients aged 10 years or less, falling progressively to 1.3% in 79 patients over 20 years of age. If the frequency of the Bf Fl and Sl factors are combined we find a decline from 23.4% in the youngest to 2.5% in the oldest group, compared with 3.2% among controls. The relative risk for Bf Fl+ Sl1 is 9.4 in patients 10 years or younger. Age-dependent relative risks in IDDM have peviously been reported2 for HLA Bwl5. In our own series relevant HLA data are available for 148 of the IDDM patients. There is no significant difference in the frequency of B8 for patients in the various age categories, but for Bwl5, 14% (13/93) are in the 0-10 age’group and 9.3 (5/54) are in the 10-20 age group. The numbers are small but the trend is in the same direction as that
age to
frequency
of
rare
Bf factors in 281 Aus-
tralian IDDM patients.
The rapid decline in the frequency of Bf F1with increasing age of patients with IDDM is compatible with a viral stimulus for initiating the disease process. If Bf Fl is in positive linkage disequilibrium for a susceptibility allele then young children carrying the Fl allele are more likely not to resist an infection, with consequent development of autoimmune responses and islet-cell destruction. With increasing age the development of partial immunity in the child population may reduce the strength of the interaction between the precipitating agent and factors linked to the susceptibility allele. In our laboratories we have demonstrated also a high frequency of lymphocytotoxins (LCs) in sera of patients with IDDM. There is a strong association between the presence of LCs and HLA type: they were present in 37% of patients homozygous for either B8 or Bwl5 compared with 16% in those not homozygous for either. A similar relationship is present for LCs and Bf factors: they were present in 38% of patients with the Bf Fl factor compared with 17% in patients without this factor. Since in our data Bf Fl is in strong negative disequilibrium with HLA-B8,3 this relationship between LCs and Bf Fl is not due to the similar relationship between
LCs and HLA-B8. Islet-cell antibodies are also more frequent in sera of IDDM patients who are HLA-B8and this relationship is even stronger in those patients in whom islet-cell antibodies have persisted for 5 years or more. We are now investigating the relationship between the frequency of Fland Sland age of the patient, together with the ’significant association between Fl and the presence of lymphocytotoxins, suggest that Bf typing will be of increasing importance in differentiating various factors in the aetiology and progress of insulin-dependent diabetes. -
Human Biology Department, John Curtin School of Medical Research, Canberra, Australia
R. L. KIRK S. W. SERJEANTSON
JAYA THEOPHILUS P. ZIMMET S. WHITEHOUSE
Royal SouthernMemorialHospital,
of Dausset.1
Melbourne
5. de Freitas
JL, Borst J, Meenhorst PL. Easy visualisation of Legionella pneumophila by"halfa Gram" stain procedure. Lancet 1979; i: 270-71. 6. Rodgers FG. Staining of Legionella pneumophila. Lancet 1979; i: 551. 1. Raum D, Alper CA, Stern R, Gabbey KH. Genetic marker for insulin-dependent diabetes mellitus. Lancet 1979; i: 1208-09. 2. Dausset J. In: HLA and disease. Dausset J, Svejgaard A, eds. Copenhagen;
Munksgaard,
Relationship of
1977: 296.
Royal Children’sHospital,
J. M. COURT
Melbourne
3. Kirk
RL, Theophilus J, press). 4. Morris, PJ, Vaughan H,
Whitehouse S, Court
JM,
Zimmet P. Diabetes
(in
Irvine WJ, et al. HLA and pancreatic islet cell antibodies in diabetes. Lancer 1976; ii: 652-53.