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Keywords:

  • HLA;
  • HPA1a;
  • immune response;
  • RhD

Abstract

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

Antibodies are friends and foes in transfusion medicine; friends as diagnostic tools and as naturally occurring antibodies in healthy individuals, foes as alloantibodies or autoantibodies. In order for antibodies to appear, a complex immune response must have taken place. This regularly involves cells and molecules belonging to the innate and adaptive immune systems. The border between the innate and adaptive immune systems is not obvious and the two cannot be regarded as separate systems, but rather as two sequences of the same response. There are few if any immune responses belonging to the field of transfusion medicine that is described in detail from the first contact with the innate immune system all the way to the functional immune response. The most ‘complete’ immune responses are described to infectious agents. Immune responses will be discussed in general and with special focus on responses to foreign human leucocyte antigens (HLA), to RhD – and human platelet antigen (HPA) 1a, which are all strong antigens related to the field of transfusion medicine.


The immune response in general

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

Foreign material can be recognized and destroyed by non-specific mechanisms in the innate immune system like phagocytosis by granulocytes or after activation of the complement cascade via the alternative pathway or the mannose binding pathway. Immune responses are triggered by foreign antigen recognized by pattern-recognition receptors belonging to the innate immune system. These receptors recognize molecular patterns, which are common in micro-organisms [1]. There is evidence that some of these receptors recognise patterns, which are related to allo- or autoantigens [2]. Engagement of pattern of recognition receptors activates the cell and transcription of cytokines is induced. In Fig. 1, the pattern of recognition receptor is located on an antigen-presenting cell (APC). Engagement of the receptor will induce cytokine production and influence the maturation of the APC, which could be dendritic cells. The maturation stage of dendritic cells influence the presentation of antigens for T-cells and the differentiation of T cells into activated T cells or regulatory T cells [1]. Simultaneously, B cells will recognize soluble antigens from the same micro-organism and the activated B cell will get help from activated CD4 T cell for differentiation to antibody producing plasma cell. The antibodies will recognize soluble antigens with the same epitope as the antigen, which initially activated the B cell, and will, dependent on antibody class and isotype, eliminate the antigens by Fc mediated phagocytosis, opsonization, complement activation, neutralization, antibody dependent cytotoxicity (via NK cells), induction of apoptosis or inhibition of proliferation. The CD4 positive T cells will in addition to provide B-cell help, activate macrophages to produce pro-inflammatory cytokines and to kill intracellular micro-organisms more efficiently. Also, in case of intracellular antigens, CD4 T cells will help CD8 T cells to kill cells presenting foreign antigens in the context of HLA class I. One effect of activation of B and T cells is asymmetric cell division and creation of memory cells. The ultimate goal is to eliminate the antigen, recreate a normal and healthy situation and establish memory for the unique immune response.

image

Figure 1.  The figure shows the process of eliminating antigens by collaboration between cells and molecules belonging to the innate and adaptive immune systems. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology, Regulatory T cells: friend or foe in immunity to infection? © 2004 [1]. http://www.nature.com

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The cells in the immune response

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

All the cells differentiated from the haematopoietic stem cell, perhaps with the exception of red cells, have been described as active participants in the immune response. Platelets are shown to be active both as producers of cytokines and as participants in the transfusion-related immune-modulation that has been described as an effect of white blood cells in the transfused blood [3].

Immune responses related to transfusion, pregnancy and transplantation

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

In transfusion medicine, a lot of attention is paid to naturally occurring antibodies, most typically anti-A and anti-B. These antibodies are absent in newborn and occur in the first months after birth probably as antibodies to epitopes on normal intestinal bacteria. The antibodies are cross reacting with blood group A and B antigens that the individual is lacking. This points to the phenomenon of tolerance to self-antigens; a person with blood type A will have naturally occurring antibodies to the B-antigen. These antibodies are of IgM class, the antigens are of carbohydrate nature and cannot be presented by T cells; the B cells are T cell independent (B1 cells). These cells do not differentiate to memory cells and the plasma cells are short-lived, indicating ongoing B-cell stimulations throughout life. As IgM efficiently activate complement, anti-A can easily induce lysis of cells with A-antigen on the surface.

Transfusion and pregnancy regularly expose individuals for foreign blood cell antigens. There are more than 30 blood type systems and hundreds of epitopes. In transfusion medicine, simple blood typing of ABO antigens and RhD is performed before transfusion and compatible blood product to these antigens are chosen. Pregnancies occur without considering blood type compatibility between mother and father. Both upon blood transfusions and in pregnancies, there will always be non-compatibility for some antigens and susceptibility for immunization. The immunogenicity of blood group antigens varies and the ability to immunize is not only related to the nature of the antigen, but also the HLA class II molecules and other gene product are of importance for the immune response. Immunization with A- and B-antigens will not be discussed in further details. RhD, HPA1a and HLA class I antigens are strong antigens and immunization is of importance in transfusion medicine. The pathophysiology of the immune responses is relatively well described.

RhD immunization

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

RhD immunization takes place in approximately 50–85% of Caucasians after repeated incompatible transfusions [4]. As many patients do not make antibodies, other factors than the antigen itself are of importance, for instance the HLA class II type. In the laboratory, anti-D antibodies are measured. The T cells participating in the immune response have got some attention [5]. The RhD immunization related to incompatible pregnancies is rare after introduction of prenatal and/or postnatal injections of anti-D in RhD negative women. The function of the injected anti-D is not fully understood, but it is clear that sensitized red cells bind to Fcγ receptors on macrophages in the spleen and are removed from the circulation and made non-immunogenic [6].

Anti-D antibodies do not activate complement. The haemolysis of sensitized red cells takes place outside the blood vessels in splenic macrophages. If the haemolysis of red blood cells in the foetus exceeds the production, the foetus may become severely anaemic; at the same time, there is a suppression of albumin production and the foetus will become oedemic (haemolytic disease of the newborn, HDN).

The anti-D antibodies given to RhD negative pregnant women and mothers are made by immunization of volunteer male donors. Attempts to make monoclonal or recombinant anti-D antibodies have so far not succeeded [7]. The details of immune response to anti-D are not fully understood even if the phenomenon of RhD immunization in pregnancy has been known since 1939 [8].

HPA1a immunization

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

The correlation between thrombocytopenia in the newborn and incompatibility between mother and child in the human platelet antigen (HPA)-1 system has been known since 1953 [9]. Among antigens specific to platelets, HPA1a is the most immunogenic being the basis for more than 80% of the cases of neonatal alloimmune thrombocytopenia (NAIT). The pathophysiology of NAIT is similar to HDN, the thrombocytopenia can result in haemorrhage. Intracranial haemorrhage can be fatal or result in severe disability. Part of the immune response in NAIT is known. The anti-HPA 1a antibodies are of IgG class and the level of antibodies in the mother correlates to the severity of thrombocytopenia in the foetus [10–13]. One report does not support this finding [14]. HPA1a specific T cells have been identified [15] and it is known that a specific HLA class II molecule (HLA DRB3*0101) most efficiently present the peptide for T cells. The most immunogenic peptide is described [16]. There is no published information about the relationship between the innate immune response and the adaptive part, to the HPA1a antigen.

HLA immunization

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

Antibodies to HLA class I can be detected after pregnancy [17] and after transfusion of different types of blood products containing leucocytes. One clinical effect of anti-HLA class I antibodies, is refractoriness to platelet transfusions. In the pregnancy, HLA class I antibodies are not known to cause disease in the foetus or newborn although thrombocytopenia is described to be caused by these antibodies [18]. Since HLA class I is present on all nucleated cells and platelets, it is believed that the antibodies will not bind in high enough number on any cell to cause cell lysis. Platelets may be an exception.

HLA antigens are strong allo-antigens and 10% of the T cells have T-cell receptors recognizing these antigens. There are two modes of immunization; by direct or indirect allo-recognition. In direct allo-recognition, HLA class I and II molecules on the surface of donor cells are recognized by recipient CD4 and CD8 positive T cells without processing or presentation by recipient HLA molecules. In indirect recognition, donor cells are taken up by recipient APCs, processed and presented by recipient HLA class I or II molecules. In both cases, CD4 and CD8 T cells are activated. At the same time, soluble antigens are recognized by B cells and with T-cell help, the B cells differentiate to plasma cells producing HLA antibodies. HLA class I antibodies are most destructive because of the wide distribution of HLA class I molecules.

HLA class I antibodies can be responsible for refractoriness to platelet transfusion and create problems in the field of transplantation. Leuco-filtration of blood products has reduced the number of HLA immunized patients after transfusions. Women are still susceptible to immunization in pregnancies.

Future

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References

To prevent immunization due to blood group antigens or HLA molecules or to ‘treat’ patients who have already been immunized, the immune responses have to be understood in detail. There is hardly any knowledge about the innate immune response to RhD, HPA1 and HLA-antigens, but increasing knowledge about the interactions between antigen-presenting cells, B cells and T cells. Detailed knowledge about the different parts of the antibodies both related to antigen binding and functional aspect may contribute to creation of recombinant ‘smart’ antibodies for prevention of immunization or for neutralization of antibodies in individuals who are already immunized [19,20]. Also peptides have been made in attempts to induce tolerance for HPA-1a antigens in immunized HPA-1bb women [16]. Induction of tolerance to HLA antigens has been tried by repeated transfusions of leucocytes from father to mother in cases of habitual abortion and high level of HLA class I antibodies with variable success [21].

Immune modulation is an attempt to regulate immune responses and may thus be a mechanism to overcome immune mediated pathology. An absolute prerequisite for successful immune modulation is to understand the immune response in every detail. It is hard and difficult work, but scientists must be determined and never give up understanding the nature of the immune response.

References

  1. Top of page
  2. Abstract
  3. The immune response in general
  4. The cells in the immune response
  5. Immune responses related to transfusion, pregnancy and transplantation
  6. RhD immunization
  7. HPA1a immunization
  8. HLA immunization
  9. Future
  10. References