- Email: [email protected]
CELLULAR BASIS OF IMMUNE RESPONSE TO ANTIGENS OF ABO BLOOD-GROUP SYSTEM
1369
9th day after infection, probably as a result of degradation of the drug. Using a two-dose schedule (additional drug added on day 1 and day 5) with 30 !1g/ml, 50 g/ml, and 70 tg/ml, we obtained a dose response similar to that shown in fig 2 (data not shown). Replacing the medium and drug after 5 days delayed but did not eliminate the eventual appearance of RT. 9 to 10 days after infection, counts were greater than 10 000 with all three drug concentrations, although the counts of infected cells plus 30 g/ml were twice as high as the counts of infected cells plus 70 g/ml. In the second experiment, we examined whether the drug had its effect on viral replication or on cellular function. We incubated uninfected cells for 7 days with 100 g/ml and 50 J.Lg/ml of ribavirin, and then washed them with medium to remove the drug. Cells were inoculated with virus, and RT levels were measured. RT levels were raised by day 5 (fig 3), indicating that ribavirin suppresses viral replication without irreversibly affecting cell function. This conclusion is further supported by the late production of RT by virus-infected cells in the presence of 50-100 g/ml of ribavirin. Our data suggest that ribavirin inhibits the replication of LAV in human adult T lymphocytes in vitro. The lowest effective in-vitro dose is in the range of 30- 50 J.Lg/ml. While it is reasonable to use in-vitro drug levels as general guidelines for effective drug dosage, the in-vivo dosage requirement may be very different. We feel that these initial data are sufficiently encouraging and the problem they address sufficiently serious to warrant an early report. However, we do not know whether these early laboratory experiments are predictive of a positive clinical effect in patients.
Hypothesis
We thank Mrs Janet Heath, Miss Neile McGrath, and Mr John Krebs for technical assistance, and Dr D. P. Francis and Dr BJ(’. R. Dowdle for reviewing
the paper Correspondence
should be addressed
to
J. B. McC.
REFERENCES 1 Vilmer
E, Barré-Sinoussi F, Rouzioux C, et al. Isolation of a new lymphotropic retrovirus from two siblings with haemophilia B, one with AIDS. Lancet 1984; i
753-57. 2. Piot P, Quinn
T, Taelman H, et al. Acquired immunodeficiency syndrome in a population in Zaire. Lancer 1984, ii 65-69. Jaffe HW, Bregman DJ, Selik RM. Acquired immune deficiency syndrome in the heterosexual
3.
United States The first 1000 cases J Infect Dis 1983, 148: 339-45. 4. Gallo R, Salahuddin S, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS Science
1984, 224: 500-03. F, Chermann JC, Rey F,
5. Barré-Sinoussi
from
a
patient
at
risk for
acquired
et
al Isolation of a
immune
T-lymphotropic retrovirus deficiency syndrome (AIDS). Science
1983, 220: 868-71. 6.
Rogers MF, Morens DM, Stewart JA, et al. National case-control study of Kaposi’s sarcoma and Pneumocystis carin pneumonia in homosexual men Part 2, laboratory
results. Ann Intern Med 1983; 99: 151-58. JT, Robins RK, Sidwell R, Simon LN. Design, synthesis and broad spectrum antiviral activity of 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem 1972, 15: 1150-54. 8. Goswami DB, Borek E, Sharma OK, Fujitaki J, Smith RA. The broad spectrum antiviral agent ribavirin inhibits capping of RNA. Biochem Biophys Res Comm 1979, 89: 83O-3 9. Sidwell R Ribavirin: In vitro antiviral activity. In: Smith RA, Kirkpatrick W, eds. Ribavirin a broad spectrum anti-viral agent. New York: Academic Press, 1980 23-42. 10. Hall CB, McBride JT, Walsh EE, et al. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. A randomized double-blind study. N Engl J 7. Witkowski
Med 1983; 308: 1443-47. 1. Knight V, McClung HW, Wilson SZ, et al Ribavirin small particle aerosol treatment of influenza. Lancet 1981, ii: 945-49 12. Gallo RC, Gallagher RE, Ruscett F In Clarkson B, Marks PA, Till JE, eds. Differentiation of normal and neoplastic hematopoietic cells. Cold Spring Harbor: Cold Spring Harbor Press, 1978; 5: 671-94. 13. Feorino P, Kalyanaraman V, Haverkos H, et al. Lymphadenopathy-associated virus infection of a blood donor-recipient pair with acquired immunodeficiency syndrome Science 1984; 225: 69-72.
substances in the environment-for example, within the of bacterial cell walls and in plant material. However, in individuals of groups A, A2, and B, this naturally occurring antibody is of the IgM class. Only in individuals of blood group 0 is immune IgG against A, A2, and B readily produced, usually after a stimulus such as injection of serum containing blood-group substance or pregnancy with a group A or B fetus. The reason for this anomaly has so far remained a mystery.2 I propose here that the anomalous serological phenomena associated with the ABO system are related to the mode of antigen recognition.
polysaccharides
CELLULAR BASIS OF IMMUNE RESPONSE TO ANTIGENS OF ABO BLOOD-GROUP SYSTEM
Capacity to Provide Help during Response to T-cell-dependent ABO-system Antigens is Restricted to Individuals of Blood Group O L. A. KAY
Department of Clinical Haematology, Royal Infirmary, Sunderland, Tyne and Wear It is postulated that the near-identity of the A and B antigens in man makes it impossible for individuals of groups A, A2, or B to provide T-cell help during a response to T-dependent non-self antigens by B2 lymphocytes. Thus, people of these groups are unable to produce immune IgG antibody. The presence of naturally occurring IgM antibody to non-self antigen from the age of 6 months is due to a separate system of T-cellindependent B 1 cells which have arisen during evolution to protect the host against polysaccharide-encapsulated bacterial pathogens.
Summary
INTRODUCTION
THE ABO system differs from all other blood-group systems in that IgM antibodies to the appropriate non-self blood groups
found from the age of 6 months in the immunocompetent subject. These antibodies are thought to arise because of the ubiquitous presence of ABH-like are
ANTIGENS OF ABO SYSTEM
Antigens that can be recognised within the ABO system exist in two major forms-non-human antigens on bacteria and other environmental materials and the human A, B, and H antigens present on group A, B, and 0 red cells and in the secretions of the 80% of people with secretor status. The non-human A, B, and H like antigens are polysaccharides consisting of simple repeating antigenic subunits. Such antigens behave independently of helper T cells (T-independent antigens) if they are ofa suitable epitope density.3 They cross-link the surface immunoglobulin molecules of the appropriate clone of Bl(T-independent) cells, triggering an antibody response directly. It is characteristic of the response to T-independent antigens that only IgM is produced. The A, B, and H antigens in man are each defined by a terminal sugar residue at the end of a common carbohydrate presursor-ie, they differ from one another by a single sugar residue. The glycoproteins on which they appear in
1370 CLONES OF ANTIGEN-REACTIVE HELPER T AND
B2 LYMPHOCYTES
PRESENT IN NORMAL INDIVIDUALS FOR ABO-SYSTEM ANTIGENS
(or B) individuals the requirement that, during T-cell-dependent response, helper T cells and In the
case
of group A
a
B cells must interact with different determinants on the same antigen cannot be met (table), because on the challenging group-B (or group-A) antigen there is only one non-self determinant. Thus, individuals of groups A and B (and their closely related groups such as Az) are "helpless" in the face of an ABO antigenic challenge and cannot produce IgG antibody. As explained previously, a rise in IgM titre due to activation of B1 cells may occur. The cellular interactions involved are illustrated in the
A=group
A
determinant; B=gioup
B
determinant; C=cross-reacting
antigen.
figure. DISCUSSION
secretions and the glycolipids bearing them on red cells do not alter their antigenicity.4 However, these human ABH antigens cannot be presented to B cells directly during an immune response. They must be processed by macrophages and presented to helper T cells in the context of class II HLA molecules. Only then can the helper T cells induce appropriate clones of type B2 lymphocytes to produce antibody. It is characteristic of the response to T-celldependent antigens that IgM is produced at first, rapidly followed by a T-cell-triggered switch to IgG production. To evoke a T-dependent response the antigenic molecules must possess at least two antigenic determinants. The T cell interacts with one determinant (carrier), the B cell with the second (hapten). The hapten and carrier must be linked on the same antigenic molecule.5propose that in certain situations blood-group antigens are unable to satisfy these requirements for T-dependent antibody responses. If T-cell-dependent antigens are cross-linked by preformed IgM antibody it is possible that they can be made to behave as
T-independent antigens, triggering
an
IgM antibody
response in type B1 cells.This would explain the rise in "natural" IgM agglutinin titres in subjects challenged with incompatible ABO blood or blood-group substance of the
T-dependent type. CELLULAR BASIS OF IMMUNE RESPONSE TO ABO-SYSTEM ANTIGENS
Response to T-independent Antigens During embryonic life clones of B1 cells to ABO-system antigens arise in people of all
the non-self ABO blood groups. These clones arise to protect the individual from pathogenic polysaccharide-encapsulated bacteria that evade macrophage ingestion and cannot be processed for T-celldependent recognition.6 The fortuitous similarity between bacterial antigens and ABO groups means that non-self ABO antibodies are present from the age of6 months.
Response to T-cell-dependent Antigens During embryonic development clones of B2 lymphocytes specific to non-self ABO groups arise. Similarly, specific T-helper clones arise. From a knowledge of the antibodies detectable in human beings the clones permitted to arise can be deduced (see table). Clones may arise to the terminal sugars defining A and B antigens and to the cross-reacting C antigen, which evokes the production of cross-reacting immune antibody in group0 subjects after antigenic challenge.The nature of the C antigen is disputed, but it may consist of part of the common carbohydrate ABH precursor plus a possible conformational change due to the presence of the A or B terminal sugar.
The hypothesis that only individuals of group 0 can respond to non-self T-cell-dependent antigens of the ABO system by IgG production is consistent with many wellknown observations. For example, it may explain why almost without exception mothers of infants with ABO haemolytic disease of the newborn are group 0.8 The observations that the firstborn is commonly affected and that a greater proportion of fathers and children are secretors than in unaffected families suggest that the mother may be sensitised by paternal AB antigen in semen or fetal AB substance. T-cell-independent ABO-like antigen from the environment would not be able to evoke the production of IgG. Individuals of groups A2 and A2B may have IgG cold antiAl in their serum. This cold agglutinin is ignored during cross-matching of blood. However, there have been a few reports of the development of rising titres of warm immune anti-AI, active at 37°C, which was presumably IgG.9,1O A common feature of these reports is that the immune type antiAl arose during multiple transfusion of blood of both grou 0 and group A. The rise in anti-AI was too great to1 accounted for by passive transfer ofanti-A; from the grou’ donors, particularly since in some of the cases descrk packed group-0 cells were used. The two examples of the phenomenon reported by Boorman et al9 (cases IV and V) are illustrative. Both women were very ill: one had extensive and tuberculosis, pulmonary lymphadenopathy, splenomegaly; the other was receiving massive doses of sulpha drugs for staphyloccal septicaemia with metastati, lung abscesses. It is therefore possible that helper 1 lymphocytes (specific to antigen C) from the group-0 donors
Hypothetical cellular response to T-dependent antigen. Panels I and 11: response of group-0 subject to group-A antigen: I-cooperation to produce anti-A ; 11-cooperation to produce anti-C. Panels III and IV: response of group-B subject to group-A antigen: III-failure to produce anti-A because appropriate T-helper clone forbidden; IV-failure to produce anti-C due to clonal deletion of appropriate B cell. A = sugar residue defining group-A specificity; C = common carbohydrate precursor; B2A=T-cell-dependent B cell with A-specific surface immunoglobulin; ThA =helper T cell with receptor for A antigen; B2C=Tcell-dependent B cell with C-antigen-specific surface immunoglobulin; The helper T cell with receptor for C antigen. =
1371
survived long enough
to
provide help
to
allogeneic anti-A 1-
specific B2 cells. T lymphocytes can survive for up to 3 weeks in blood stored at 4°C.li This finding may explain the production of IgG antibody in non-group-0 individuals. There have been reports of autoimmune type haemolysis, caused by antibodies reactive at 37°C, after transplantation of non-irradiated group-0 organs to ABO-incompatible . recipients.12-14 The phenomenon does not occur if the donor organ has been irradiated. 15 Beck et al 12 postulated that transferred group-0 lymphoreticular tissue might be responsible, in particular the B cells of the donor. Mangall6 emphasised the role of group-0 B cells, because in all the reported cases of the phenomenon in renal transplantation the immunosuppressive drug cyclosporin was used and this is known to interfere with T-cell responses to interleukin 2. According to my hypothesis, however, both T and B cells from the donor are required, since only group-0 helper T : cells are capable of inducing IgG production by B cells. It has been shown that primed helper T cells and "memory" helper T cells can respond to interleukin 2 in the presence of : cyc1osporinY Adult group-O organ donors may have been ; primed to non-self T-dependent ABO antigens by pregnancy, sexual contact, the injection of serum or transfusion of ;plasma. (Exposure to ABO antigens in the environment would not, as discussed earlier, lead to T-cell priming, since these antigens cannot be processed by macrophages for presentation to T cells.)
Methods and Devices INSPIRATION-PHASED OXYGEN DELIVERY R. J. D. WINTER J. C. MOORE-GILLON London Chest Hospital,
R. J. D. GEORGE D. M. GEDDES Bonner Road, London E2 9JX
" LoG-TER-B1 use of domiciliary oxygen in chronic bronchitis and emphysema has a beneficial effect on pulmonary haemodynamics and prolongs survival in some patients.I,2A reduction in breathlessness and an improvement in wellbeing have also been reported. Despite these advantages there is a reluctance to prescribe domiciliary oxygen, usually on grounds of cost or the inconvenience of delivery of many cylinders to the home. We describe a new device that allows inspiration-phased oxygen delivery (IPOD); we have evaluated its effects on arterial oxygen and carbon dioxide tensions (PaOz, PaCOz) and gas cost in patients who when clinically stable have a Pa02 of less than 60 mm Hg.
-
CONVERSION
Gas tensions:
1 mm 1 kPa
0.133 kPa 7.5 mm Hg
Hg =
=
The Device The IPOD device measures 12 x 10 x 7 cm and weighs 1.3 kg, the rechargeable battery (Glasrock Home Health Care, Brentford, Middlesex). As well as the battery the device contains a detector sensitive to pressure changes in excess of 0.5 Pa on the change from expiration to inspiration, monitored through a conventional nasal cannula, and a valve which opens to provide oxygen from an oxygen source when instructed to do so by the logic circuit, which ensures that oxygen is flowing to the patient 30% or more of the time, coinciding with the inspiratory part of the breathing cycle as shown in fig 1. It is intended that the final version of the device will be smaller than this prototype and that it could be attachable to the oxygen cylinder. The device is virtually silent in operation, except for the normal sound of gas delivery, and it was reliable during fairly intensive use in our study. The cost is expected to be about 150, though the device could be rented with the cylinder.
including
CONCLUSIONS AND IMPLICATIONS
If this hypothesis is correct it gives new emphasis to the nossibility that group-0 individuals are not safe universal nors. Transfusion of group-0 blood to severely :munocompromised non-group-0 patients should be or the blood should be irradiated before transfusion; 4ed from donors for
group-0 non-group-0 recipients ’,4ns ’:JUld also be irradiated before transplantation. The hypothesis that only group-0 individuals are able to .provide T-cell help during a response to non-self T-dependent ABO antigens should not be difficult to test. The antigens are readily available and can be isolated. The propriate T and B cell subsets can be separated from whole 1 :ood for in-vitro examination of their responses, and a well_characterised antigenic target exists in the red cell. The ABO system provides an accessible physiological del for the study of the human response to T-independent and T-dependent antigens. Its study in vitro should provide valuable insights into the cellular basis of the immune :
response in
man.
Fig I-Activation characteristics of the device. Upper trace = oxygen flow (pneumotachograph); pattern (inductance plethysmograph).
REFERENCES
AJ, Abelson NM. Studies of blood group antibodies. IV Physicochemical differences between isoanti A, B and isoanti-A or isoanti-B. J Immunol 1960; 85:
wson
40-47.
5 6
7 8
lison PL. Red cell antigens and antibodies-interactions In- Blood transfusion in clinical medicine, 7th ed. Oxford- Blackwell, 1983: 220-28. McConnell I, Munro A, Waldman H, eds. Chapter 8-B lymphocytes. Chapter 13-Immunological tolerance. In. The immune system, 2nd ed. Oxford: Blackwell, 1981: 131-35, 209-11. Morgan WTJ. Genetic and biochemical aspects of human blood group A-, B-, H-, Leaand Leb- specificity. Br Med Bull 1969; 25: 30-62 Coutinho A, Pober G, Petterson S, et al. T cell-dependent B cell activation. Immunol Rev 1984; 78: 211-24. Marshall-Clarke S, Playfair JHL. B cells: sub-populations, tolerance, autoimmunity and infection. Immunol Rev 1979; 43: 109-41. Mollison PL. ABO, Lewis, Li + P groups. In: Blood transfusion in clinical medicine, 7th ed. Oxford: Blackwell, 1983: 290-329. Wiener AS, Freda VJ, Wexler IB, Brancato GJ. Pathogenesis of ABO hemolytic disease. Am J Obstet Gynecol 1960; 79: 567-92
L. A. KAY 9. Boorman 10.
lower
trace=breathing
REFERENCES—continued
KE, Dodd BE, Loutit DM, Mollison PL. Some results of transfusion ofblood
to recipients with "cold" agglutinins. Br Med J 1946, i 751-54. Lundberg WB, McGinniss MH. Hemolytic transfusion reactions Transfusion 1975; 15: 1-9.
due
to anti
1 1 Mollison PL Transfusion of other blood components. In Blood transfusion
in
Al
clinical
medicine, 7th ed Oxford- Blackwell, 1983: 173-90. 12. Beck ML, Haines F, Oberman A. Unexpected serological findings following lung transplantation proceedings. 24th Annual Meeting of the American Association of Blood Banks, Chicago. 1971: 98. 13 Conteras M, Hazelhurst GR, Armitage SE. Development of"auto anti A antibodies" following alloimmunisation in an A2 recipient. Br J Haematol 1984; 55: 657-63. 14. Mangal AK, Grove GH, Sinclair M, Stillwell GF, Reeve CE, Naiman SC. Acquired hemolytic anaemia due to "auto" anti A or "auto" anti B induced by group O hemograft in renal transplant recipients. Transfusion (in press) 15. Mangal AK, Logan D, Sinclair M, Stillwell G Protection against hemolysis in ABO mismatched renal transplantation. Transfusion (in press) 16. Mangal AK, Sinclair M. Development of "auto anti-A1 antibodies" following alloimmunisation in an A2 recipient. Br J Haematol 1984; 57: 714-15. 17 Britton S, Palacios R. Cyclosporin A-usefulness, risks and mechanism of action. Immunol Rev 1982, 65: 5-22.
9th day after infection, probably as a result of degradation of the drug. Using a two-dose schedule (additional drug added on day 1 and day 5) with 30 !1g/ml, 50 g/ml, and 70 tg/ml, we obtained a dose response similar to that shown in fig 2 (data not shown). Replacing the medium and drug after 5 days delayed but did not eliminate the eventual appearance of RT. 9 to 10 days after infection, counts were greater than 10 000 with all three drug concentrations, although the counts of infected cells plus 30 g/ml were twice as high as the counts of infected cells plus 70 g/ml. In the second experiment, we examined whether the drug had its effect on viral replication or on cellular function. We incubated uninfected cells for 7 days with 100 g/ml and 50 J.Lg/ml of ribavirin, and then washed them with medium to remove the drug. Cells were inoculated with virus, and RT levels were measured. RT levels were raised by day 5 (fig 3), indicating that ribavirin suppresses viral replication without irreversibly affecting cell function. This conclusion is further supported by the late production of RT by virus-infected cells in the presence of 50-100 g/ml of ribavirin. Our data suggest that ribavirin inhibits the replication of LAV in human adult T lymphocytes in vitro. The lowest effective in-vitro dose is in the range of 30- 50 J.Lg/ml. While it is reasonable to use in-vitro drug levels as general guidelines for effective drug dosage, the in-vivo dosage requirement may be very different. We feel that these initial data are sufficiently encouraging and the problem they address sufficiently serious to warrant an early report. However, we do not know whether these early laboratory experiments are predictive of a positive clinical effect in patients.
Hypothesis
We thank Mrs Janet Heath, Miss Neile McGrath, and Mr John Krebs for technical assistance, and Dr D. P. Francis and Dr BJ(’. R. Dowdle for reviewing
the paper Correspondence
should be addressed
to
J. B. McC.
REFERENCES 1 Vilmer
E, Barré-Sinoussi F, Rouzioux C, et al. Isolation of a new lymphotropic retrovirus from two siblings with haemophilia B, one with AIDS. Lancet 1984; i
753-57. 2. Piot P, Quinn
T, Taelman H, et al. Acquired immunodeficiency syndrome in a population in Zaire. Lancer 1984, ii 65-69. Jaffe HW, Bregman DJ, Selik RM. Acquired immune deficiency syndrome in the heterosexual
3.
United States The first 1000 cases J Infect Dis 1983, 148: 339-45. 4. Gallo R, Salahuddin S, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS Science
1984, 224: 500-03. F, Chermann JC, Rey F,
5. Barré-Sinoussi
from
a
patient
at
risk for
acquired
et
al Isolation of a
immune
T-lymphotropic retrovirus deficiency syndrome (AIDS). Science
1983, 220: 868-71. 6.
Rogers MF, Morens DM, Stewart JA, et al. National case-control study of Kaposi’s sarcoma and Pneumocystis carin pneumonia in homosexual men Part 2, laboratory
results. Ann Intern Med 1983; 99: 151-58. JT, Robins RK, Sidwell R, Simon LN. Design, synthesis and broad spectrum antiviral activity of 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem 1972, 15: 1150-54. 8. Goswami DB, Borek E, Sharma OK, Fujitaki J, Smith RA. The broad spectrum antiviral agent ribavirin inhibits capping of RNA. Biochem Biophys Res Comm 1979, 89: 83O-3 9. Sidwell R Ribavirin: In vitro antiviral activity. In: Smith RA, Kirkpatrick W, eds. Ribavirin a broad spectrum anti-viral agent. New York: Academic Press, 1980 23-42. 10. Hall CB, McBride JT, Walsh EE, et al. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. A randomized double-blind study. N Engl J 7. Witkowski
Med 1983; 308: 1443-47. 1. Knight V, McClung HW, Wilson SZ, et al Ribavirin small particle aerosol treatment of influenza. Lancet 1981, ii: 945-49 12. Gallo RC, Gallagher RE, Ruscett F In Clarkson B, Marks PA, Till JE, eds. Differentiation of normal and neoplastic hematopoietic cells. Cold Spring Harbor: Cold Spring Harbor Press, 1978; 5: 671-94. 13. Feorino P, Kalyanaraman V, Haverkos H, et al. Lymphadenopathy-associated virus infection of a blood donor-recipient pair with acquired immunodeficiency syndrome Science 1984; 225: 69-72.
substances in the environment-for example, within the of bacterial cell walls and in plant material. However, in individuals of groups A, A2, and B, this naturally occurring antibody is of the IgM class. Only in individuals of blood group 0 is immune IgG against A, A2, and B readily produced, usually after a stimulus such as injection of serum containing blood-group substance or pregnancy with a group A or B fetus. The reason for this anomaly has so far remained a mystery.2 I propose here that the anomalous serological phenomena associated with the ABO system are related to the mode of antigen recognition.
polysaccharides
CELLULAR BASIS OF IMMUNE RESPONSE TO ANTIGENS OF ABO BLOOD-GROUP SYSTEM
Capacity to Provide Help during Response to T-cell-dependent ABO-system Antigens is Restricted to Individuals of Blood Group O L. A. KAY
Department of Clinical Haematology, Royal Infirmary, Sunderland, Tyne and Wear It is postulated that the near-identity of the A and B antigens in man makes it impossible for individuals of groups A, A2, or B to provide T-cell help during a response to T-dependent non-self antigens by B2 lymphocytes. Thus, people of these groups are unable to produce immune IgG antibody. The presence of naturally occurring IgM antibody to non-self antigen from the age of 6 months is due to a separate system of T-cellindependent B 1 cells which have arisen during evolution to protect the host against polysaccharide-encapsulated bacterial pathogens.
Summary
INTRODUCTION
THE ABO system differs from all other blood-group systems in that IgM antibodies to the appropriate non-self blood groups
found from the age of 6 months in the immunocompetent subject. These antibodies are thought to arise because of the ubiquitous presence of ABH-like are
ANTIGENS OF ABO SYSTEM
Antigens that can be recognised within the ABO system exist in two major forms-non-human antigens on bacteria and other environmental materials and the human A, B, and H antigens present on group A, B, and 0 red cells and in the secretions of the 80% of people with secretor status. The non-human A, B, and H like antigens are polysaccharides consisting of simple repeating antigenic subunits. Such antigens behave independently of helper T cells (T-independent antigens) if they are ofa suitable epitope density.3 They cross-link the surface immunoglobulin molecules of the appropriate clone of Bl(T-independent) cells, triggering an antibody response directly. It is characteristic of the response to T-independent antigens that only IgM is produced. The A, B, and H antigens in man are each defined by a terminal sugar residue at the end of a common carbohydrate presursor-ie, they differ from one another by a single sugar residue. The glycoproteins on which they appear in
1370 CLONES OF ANTIGEN-REACTIVE HELPER T AND
B2 LYMPHOCYTES
PRESENT IN NORMAL INDIVIDUALS FOR ABO-SYSTEM ANTIGENS
(or B) individuals the requirement that, during T-cell-dependent response, helper T cells and In the
case
of group A
a
B cells must interact with different determinants on the same antigen cannot be met (table), because on the challenging group-B (or group-A) antigen there is only one non-self determinant. Thus, individuals of groups A and B (and their closely related groups such as Az) are "helpless" in the face of an ABO antigenic challenge and cannot produce IgG antibody. As explained previously, a rise in IgM titre due to activation of B1 cells may occur. The cellular interactions involved are illustrated in the
A=group
A
determinant; B=gioup
B
determinant; C=cross-reacting
antigen.
figure. DISCUSSION
secretions and the glycolipids bearing them on red cells do not alter their antigenicity.4 However, these human ABH antigens cannot be presented to B cells directly during an immune response. They must be processed by macrophages and presented to helper T cells in the context of class II HLA molecules. Only then can the helper T cells induce appropriate clones of type B2 lymphocytes to produce antibody. It is characteristic of the response to T-celldependent antigens that IgM is produced at first, rapidly followed by a T-cell-triggered switch to IgG production. To evoke a T-dependent response the antigenic molecules must possess at least two antigenic determinants. The T cell interacts with one determinant (carrier), the B cell with the second (hapten). The hapten and carrier must be linked on the same antigenic molecule.5propose that in certain situations blood-group antigens are unable to satisfy these requirements for T-dependent antibody responses. If T-cell-dependent antigens are cross-linked by preformed IgM antibody it is possible that they can be made to behave as
T-independent antigens, triggering
an
IgM antibody
response in type B1 cells.This would explain the rise in "natural" IgM agglutinin titres in subjects challenged with incompatible ABO blood or blood-group substance of the
T-dependent type. CELLULAR BASIS OF IMMUNE RESPONSE TO ABO-SYSTEM ANTIGENS
Response to T-independent Antigens During embryonic life clones of B1 cells to ABO-system antigens arise in people of all
the non-self ABO blood groups. These clones arise to protect the individual from pathogenic polysaccharide-encapsulated bacteria that evade macrophage ingestion and cannot be processed for T-celldependent recognition.6 The fortuitous similarity between bacterial antigens and ABO groups means that non-self ABO antibodies are present from the age of6 months.
Response to T-cell-dependent Antigens During embryonic development clones of B2 lymphocytes specific to non-self ABO groups arise. Similarly, specific T-helper clones arise. From a knowledge of the antibodies detectable in human beings the clones permitted to arise can be deduced (see table). Clones may arise to the terminal sugars defining A and B antigens and to the cross-reacting C antigen, which evokes the production of cross-reacting immune antibody in group0 subjects after antigenic challenge.The nature of the C antigen is disputed, but it may consist of part of the common carbohydrate ABH precursor plus a possible conformational change due to the presence of the A or B terminal sugar.
The hypothesis that only individuals of group 0 can respond to non-self T-cell-dependent antigens of the ABO system by IgG production is consistent with many wellknown observations. For example, it may explain why almost without exception mothers of infants with ABO haemolytic disease of the newborn are group 0.8 The observations that the firstborn is commonly affected and that a greater proportion of fathers and children are secretors than in unaffected families suggest that the mother may be sensitised by paternal AB antigen in semen or fetal AB substance. T-cell-independent ABO-like antigen from the environment would not be able to evoke the production of IgG. Individuals of groups A2 and A2B may have IgG cold antiAl in their serum. This cold agglutinin is ignored during cross-matching of blood. However, there have been a few reports of the development of rising titres of warm immune anti-AI, active at 37°C, which was presumably IgG.9,1O A common feature of these reports is that the immune type antiAl arose during multiple transfusion of blood of both grou 0 and group A. The rise in anti-AI was too great to1 accounted for by passive transfer ofanti-A; from the grou’ donors, particularly since in some of the cases descrk packed group-0 cells were used. The two examples of the phenomenon reported by Boorman et al9 (cases IV and V) are illustrative. Both women were very ill: one had extensive and tuberculosis, pulmonary lymphadenopathy, splenomegaly; the other was receiving massive doses of sulpha drugs for staphyloccal septicaemia with metastati, lung abscesses. It is therefore possible that helper 1 lymphocytes (specific to antigen C) from the group-0 donors
Hypothetical cellular response to T-dependent antigen. Panels I and 11: response of group-0 subject to group-A antigen: I-cooperation to produce anti-A ; 11-cooperation to produce anti-C. Panels III and IV: response of group-B subject to group-A antigen: III-failure to produce anti-A because appropriate T-helper clone forbidden; IV-failure to produce anti-C due to clonal deletion of appropriate B cell. A = sugar residue defining group-A specificity; C = common carbohydrate precursor; B2A=T-cell-dependent B cell with A-specific surface immunoglobulin; ThA =helper T cell with receptor for A antigen; B2C=Tcell-dependent B cell with C-antigen-specific surface immunoglobulin; The helper T cell with receptor for C antigen. =
1371
survived long enough
to
provide help
to
allogeneic anti-A 1-
specific B2 cells. T lymphocytes can survive for up to 3 weeks in blood stored at 4°C.li This finding may explain the production of IgG antibody in non-group-0 individuals. There have been reports of autoimmune type haemolysis, caused by antibodies reactive at 37°C, after transplantation of non-irradiated group-0 organs to ABO-incompatible . recipients.12-14 The phenomenon does not occur if the donor organ has been irradiated. 15 Beck et al 12 postulated that transferred group-0 lymphoreticular tissue might be responsible, in particular the B cells of the donor. Mangall6 emphasised the role of group-0 B cells, because in all the reported cases of the phenomenon in renal transplantation the immunosuppressive drug cyclosporin was used and this is known to interfere with T-cell responses to interleukin 2. According to my hypothesis, however, both T and B cells from the donor are required, since only group-0 helper T : cells are capable of inducing IgG production by B cells. It has been shown that primed helper T cells and "memory" helper T cells can respond to interleukin 2 in the presence of : cyc1osporinY Adult group-O organ donors may have been ; primed to non-self T-dependent ABO antigens by pregnancy, sexual contact, the injection of serum or transfusion of ;plasma. (Exposure to ABO antigens in the environment would not, as discussed earlier, lead to T-cell priming, since these antigens cannot be processed by macrophages for presentation to T cells.)
Methods and Devices INSPIRATION-PHASED OXYGEN DELIVERY R. J. D. WINTER J. C. MOORE-GILLON London Chest Hospital,
R. J. D. GEORGE D. M. GEDDES Bonner Road, London E2 9JX
" LoG-TER-B1 use of domiciliary oxygen in chronic bronchitis and emphysema has a beneficial effect on pulmonary haemodynamics and prolongs survival in some patients.I,2A reduction in breathlessness and an improvement in wellbeing have also been reported. Despite these advantages there is a reluctance to prescribe domiciliary oxygen, usually on grounds of cost or the inconvenience of delivery of many cylinders to the home. We describe a new device that allows inspiration-phased oxygen delivery (IPOD); we have evaluated its effects on arterial oxygen and carbon dioxide tensions (PaOz, PaCOz) and gas cost in patients who when clinically stable have a Pa02 of less than 60 mm Hg.
-
CONVERSION
Gas tensions:
1 mm 1 kPa
0.133 kPa 7.5 mm Hg
Hg =
=
The Device The IPOD device measures 12 x 10 x 7 cm and weighs 1.3 kg, the rechargeable battery (Glasrock Home Health Care, Brentford, Middlesex). As well as the battery the device contains a detector sensitive to pressure changes in excess of 0.5 Pa on the change from expiration to inspiration, monitored through a conventional nasal cannula, and a valve which opens to provide oxygen from an oxygen source when instructed to do so by the logic circuit, which ensures that oxygen is flowing to the patient 30% or more of the time, coinciding with the inspiratory part of the breathing cycle as shown in fig 1. It is intended that the final version of the device will be smaller than this prototype and that it could be attachable to the oxygen cylinder. The device is virtually silent in operation, except for the normal sound of gas delivery, and it was reliable during fairly intensive use in our study. The cost is expected to be about 150, though the device could be rented with the cylinder.
including
CONCLUSIONS AND IMPLICATIONS
If this hypothesis is correct it gives new emphasis to the nossibility that group-0 individuals are not safe universal nors. Transfusion of group-0 blood to severely :munocompromised non-group-0 patients should be or the blood should be irradiated before transfusion; 4ed from donors for
group-0 non-group-0 recipients ’,4ns ’:JUld also be irradiated before transplantation. The hypothesis that only group-0 individuals are able to .provide T-cell help during a response to non-self T-dependent ABO antigens should not be difficult to test. The antigens are readily available and can be isolated. The propriate T and B cell subsets can be separated from whole 1 :ood for in-vitro examination of their responses, and a well_characterised antigenic target exists in the red cell. The ABO system provides an accessible physiological del for the study of the human response to T-independent and T-dependent antigens. Its study in vitro should provide valuable insights into the cellular basis of the immune :
response in
man.
Fig I-Activation characteristics of the device. Upper trace = oxygen flow (pneumotachograph); pattern (inductance plethysmograph).
REFERENCES
AJ, Abelson NM. Studies of blood group antibodies. IV Physicochemical differences between isoanti A, B and isoanti-A or isoanti-B. J Immunol 1960; 85:
wson
40-47.
5 6
7 8
lison PL. Red cell antigens and antibodies-interactions In- Blood transfusion in clinical medicine, 7th ed. Oxford- Blackwell, 1983: 220-28. McConnell I, Munro A, Waldman H, eds. Chapter 8-B lymphocytes. Chapter 13-Immunological tolerance. In. The immune system, 2nd ed. Oxford: Blackwell, 1981: 131-35, 209-11. Morgan WTJ. Genetic and biochemical aspects of human blood group A-, B-, H-, Leaand Leb- specificity. Br Med Bull 1969; 25: 30-62 Coutinho A, Pober G, Petterson S, et al. T cell-dependent B cell activation. Immunol Rev 1984; 78: 211-24. Marshall-Clarke S, Playfair JHL. B cells: sub-populations, tolerance, autoimmunity and infection. Immunol Rev 1979; 43: 109-41. Mollison PL. ABO, Lewis, Li + P groups. In: Blood transfusion in clinical medicine, 7th ed. Oxford: Blackwell, 1983: 290-329. Wiener AS, Freda VJ, Wexler IB, Brancato GJ. Pathogenesis of ABO hemolytic disease. Am J Obstet Gynecol 1960; 79: 567-92
L. A. KAY 9. Boorman 10.
lower
trace=breathing
REFERENCES—continued
KE, Dodd BE, Loutit DM, Mollison PL. Some results of transfusion ofblood
to recipients with "cold" agglutinins. Br Med J 1946, i 751-54. Lundberg WB, McGinniss MH. Hemolytic transfusion reactions Transfusion 1975; 15: 1-9.
due
to anti
1 1 Mollison PL Transfusion of other blood components. In Blood transfusion
in
Al
clinical
medicine, 7th ed Oxford- Blackwell, 1983: 173-90. 12. Beck ML, Haines F, Oberman A. Unexpected serological findings following lung transplantation proceedings. 24th Annual Meeting of the American Association of Blood Banks, Chicago. 1971: 98. 13 Conteras M, Hazelhurst GR, Armitage SE. Development of"auto anti A antibodies" following alloimmunisation in an A2 recipient. Br J Haematol 1984; 55: 657-63. 14. Mangal AK, Grove GH, Sinclair M, Stillwell GF, Reeve CE, Naiman SC. Acquired hemolytic anaemia due to "auto" anti A or "auto" anti B induced by group O hemograft in renal transplant recipients. Transfusion (in press) 15. Mangal AK, Logan D, Sinclair M, Stillwell G Protection against hemolysis in ABO mismatched renal transplantation. Transfusion (in press) 16. Mangal AK, Sinclair M. Development of "auto anti-A1 antibodies" following alloimmunisation in an A2 recipient. Br J Haematol 1984; 57: 714-15. 17 Britton S, Palacios R. Cyclosporin A-usefulness, risks and mechanism of action. Immunol Rev 1982, 65: 5-22.