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Hematologic Diseases: Autoimmune Hemolytic Anemia and Immune Thrombocytopenic Purpura

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Autoimmune destruction of circulating blood cells in autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) is often seen in autoimmune diseases and lymhoid malignancies. Erythrocytes or platelets that are recognized by autoantibodies are rapidly phagocytosed by macrophages. Although much is known about the mechanisms behind macrophage-mediated destruction of sensitized blood cells, less is known about the genetics behind AIHA and ITP. We here review what is known about the ethiology of AIHA and ITP, with particular emphasis on the role of genetic factors behind autoantibody production, T cell activation and apoptosis, and Fcγ receptor polymorphisms. The importance of inhibitory regulation of macrophages through CD47/SIRPα interaction, and its significance for autoimmune hematological disease is also discussed.

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is defined as an increased destruction of erythrocytes due to the presence of anti-erythrocyte autoantibodies (AEA) and can be classified as either autoimmune, alloimmune, or drug-induced depending on the type of antigen giving rise to the immune response.1,2 General hemolytic anemia is estimated to occur in about 4 cases per 1000 per year, but for AIHA the annual incidence is estimated to about 1-3 cases per 100,000 per year.3,4 Thus, AIHA is a rather rare disease, which can affect infants to the elderly but the majority of the patients are over the age of 40 years, with peak incidence at 70.4 AIHA can appear either as a primary disease or, in about 20-80% of the cases, secondary to other autoimmune diseases, lymphoid malignancies, infections, immunodeficiencies, or tumors, where lymphoid malignancies are the most common reasons for secondary AIHA.5,6 AEA are classified as cold or warm autoantibodies, as they react optimally at temperatures below 30°C or at 35°C to 40°C respectively.1 Warm AEA are mostly IgG but sometimes IgA and/or IgM are also present, and are responsible for about 50-70% of AIHA cases.1 The binding of warm IgG AEA to erythrocytes does not itself damage the erythrocytes, since erythrocyte bound IgG, in contrast to surface bound IgM, is a poor activator of the classical complement pathway.1 Instead, surface bound IgG is usually recognized by Fcγ receptors of cells of the monocyte-macrophage phagocytic system, preferentially in the spleen and liver, resulting in uptake and destruction of IgG-opsonized erythrocytes (fig.1).7-9 However, macrophage-mediated elimination of erythrocytes in AIHA is likely to be mediated by synergistic activity of macrophage Fcγ and complement receptors (recognizing complement factors C3b and C3bi), since erythrocytes opsonized with very low levels of IgG are not eliminated in vivo in the absence of complement.10 Furthermore, low levels of complement opsonization does not result in erythrocyte phagocytosis in the absence of IgG, whereas low levels of both complement and IgG-opsonization can induce efficient erythrocyte phagocytosis both in vivo and in vitro (fig.1).10-12

Figure 1. Macrophage Fcγ receptors and complement receptors act synergistically to stimulate erythrophagocytosis in AIHA.

Figure 1

Macrophage Fcγ receptors and complement receptors act synergistically to stimulate erythrophagocytosis in AIHA. In AIHA, anti-erythrocyte autoantibodies (AEA) bound the erythrocytes are recognized by macrophage Fcγ receptors (FcγR), (more...)

The etiology behind most AEA is poorly understood. However, it is likely to be the result of disrupted immune self-tolerance, or due to autoantibodies induced nonspecifically and transiently during microbial infections. A defective immune self-tolerance may be either due to a central defect during lymphocyte development, or due to a peripheral defect involving down-regulation of activated mature T and B cells.2 Today, the most common treatments for AIHA are Fc receptor-competitive by intravenous infusion of IgG (IVIG), or immunosuppressive, such as cytotoxic drugs or splenectomy.4

Immune Thrombocytopenic Purpura

Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterised by low platelet counts due to antibody-mediated destruction of platelets by macrophages.13 ITP is classified as acute or chronic, where acute ITP has a rapid onset with typical petechiae and bruises, is often preceded by an infectious illness, mainly affects young children, and normally resolves spontaneously within six months.13 Chronic ITP often has an adult onset that is more insidious than the acute form and is about two to three times as common among women as among men.13

A positive anti-platelet autoantibody test is found in about 70-80% of adults with ITP and in children with chronic ITP.14 Platelet autoantibodies are of the IgG type and are mostly directed to platelet membrane glycoproteins, including GPIIb/IIIa, GPIb-IX, and GPIa-IIa.15,16 Platelets coated with IgG autoantibodies undergo accelerated clearance through Fcγ receptor-mediated phagocytosis by macrophages, preferably in the spleen and liver.13,17,18 The reasons for the initiation of antibody production are mostly unknown, however, association between anti-platelet glycoprotein antibodies and HLA class II has been described (see below). Most patients have antibodies directed to several different platelet surface proteins. In the acute form of ITP, one might expect molecular mimicry which means that antibodies produced as a response to a pathogen may be able to cross-react with the host tissue.18 Of particular interest is the finding that some antiviral antibodies have been shown to cross-react with platelets, increasing the posibility of increased presentation of platelet antigens by MHC class II on phagocytic cells.19

Adults with diagnosed ITP are normally initially treated with corticosteroids,20 whereas this treatment, albeit often sucessful and less risky, is used to a lesser extent in childhood ITP.21 Intravenous gammaglobulin (IVIG) is another common approach in treatment of ITP, particularly for treatment of internal bleedings. IVIG has well known anti-inflammatory effects, generally attributed to the immunoglobulin G (IgG) Fc domain, which is thought to block pro-phagocytic Fc receptors on macrophages.22 However, recent data from mouse models suggests that the inhibitory effect of IVIG is to a big extent dependent on binding to, and upregulation of, the inhibitory Fcγ7RIIb receptor.23 In more severe cases of ITP, and in cases of tolerance to corticosteroids, splenectomy may be required to reduce platelet destruction.13

Genetic Control of AEA in AIHA

The autoimmune-prone mouse strain New-Zealand Black (NZB) spontaneously develops AIHA, which is associated with production of AEA, splenomegaly and other clinical features such as reduced hematocrit and increased reticulocyte count.24,25 Thus, due to its similarities with the human counterpart, and due to very limited knowledge on the immunogenetics behind human AIHA, this mouse strain has served as a model in attempts to dissect out the genetic peculiarities of AIHA. Autoimmune disease in NZB mice is inherited in a dominant fashion, but by studying crosses with nonautoimmune mouse strains, further knowledge on the genetics behind several AIHA-associated features has been generated. In this way, it was first suggested that production of AEA is under control of a single dominant gene.26,27 Thus, the single dominant AIHA susceptibility allele Aia-1 (autoimmune-anemia locus), loosely linked to the b locus of chromosome 4, was early associated with AEA.27 However, later studies in crosses between NZB and nonautoimmune-prone mouse strains (e.g., C57BL/6) suggested that the contribution of Aia-1to expression of AEA production was under the control of suppresive genes such as Aem-1 (anti-erythrocyte autoantibody modifying gene), mapped to the locus closely linked to Mup-1 on chromosome 4.28 More recently, data have been presented, which further supports that AIHA and AEA production are under multigenic control. By studying (C57BL/6 x NZB)F1 x NZB, genotyped for chromosomal microsattelite markers polymorphic between C57BL/6 and NZB strains, two potential C57BL/6 suppressive loci for AEA were identified on chromosomes 7 and 10.29 The locus on chromosome 7, designated Aem-2 (anti-erythrocyte autoantibody modifying gene-2), was found located between microsomal sattelite markers D7MIT30 and D7MIT297, and the locus Aem-3 on chromosome 10 was significantly linked to the marker D10MIT42.29 From this study it was concluded that production of AEA might be down-regulated by a combined effect of these potentially suppressive alleles.

HLA Susceptibility Genes and ITP

Although the genetic factors that can influence the development of ITP may include genes coding for HLA, T cell receptors and immunoglobulin allotypes, the underlying predisposing causes for ITP are not completely understood. In a study of Caucasian patients with chronic primary ITP, no association could be found between HLA class I or II alleles and a single immunogenic susceptibility factor.30 However, HLA-A2 appeared to be associated with ITP, particularly in female patients and in patients progressing to splenectomy.

In Japanese ITP patients, a strong association was found between anti-platelet glycoprotein autoantibodies and HLA class II genes. Anti-GPIIb-IIIa antibodies associated with DRB1*0405 and DQB1*0401, whereas anti-GPIb-IX antibodies associated with DRB1*0803 and DQB1*0601. Furthermore, a poor response to splenectomy was associated with DRB1*0405 and DQB1*0401 and anti-GPIIb-IIIa autoantibodies.31 Another study of the same ethnic population showed a significan increase of the DRB1*0410 allele, but not of other DRB1*04 alleles, in ITP patients.32 In this study, positivity for anti-GPIIb-IIIa autoantibodies was associated with HLA-DR4, but not with DRB1*0410.32 This is in consistance with findings of GPIIb-IIIa autoreactive T cells in ITP patients, T cells which were capable to stimulate a HLA-DR-restricted B cell production of anti-platelet antibodies.33

Genetic Alterations in the Control of T Cell Activation

T cell antigen responses are activated by interaction between the T cell receptor (TCR) and peptide/MHC complex of the antigen presenting cell (APC), with additional costimulatory signals generated by T cell CD28 interacting with the costimulatory molecule B7 expressed by APCs. These two signals are both required for T cell activation (fig.2).34,35 However, the T cell response to antigen is also under inhibitory control by CTLA-4, a molecule expressed on the surface of T cells following activation.36 Due to a higher affinity for the costimulatory molecule B7, CTLA-4 inhibits T cell proliferation by reducing CD28/B7 interactions. Since CTLA-4-deficient mice show severe autoimmune tissue destruction,36 and CTLA-4 is deficiently expressed in the diabetes-prone nonobese diabetic mice,37 it is likely that CTLA-4 is of major importance in the pathogenesis of autoimmune diseases. A high prevalence of an A to G polymorphism at position 49 of the CTLA-4 first exon, resulting in a Thr-Ala amino acid substitution at codon 17 of the CTLA-4 leader peptide, has been associated with increased susceptibility to autoimmune diseases such as insulin-dependent diabetes, Graves' disease, rheumatoid arthritis, multiple sclerosis, and also systemic lupus erythematosis.38-40 More recently, the G allele of CTLA-4 was also found to predispose to the development of AIHA. This association was found to be highest in patients with chronic lymphocytic leukemia, who subsequently developed AIHA.41 In contrast, A to G polymorphism has not been found to be associated with ITP.

Figure 2. Receptor-mediated control of T cell activation.

Figure 2

Receptor-mediated control of T cell activation. Activation of T cell antigen responses is stimulated by the T cell receptor (TCR) in contact with the antigen peptide (P) presented by major histocompatibility receptors (MHC) on the surface of antigen presenting (more...)

Defective Lymphocyte Apoptosis

During early T cell differentiation in the thymus, self-reactive T cell clones are deleted on contact with thymic antigens. However, self-reactive mature T cells encountering self-antigens in the periphery must be deleted to avoid autoimmune disease. The elimination of self-reactive mature T cells is mediated by a number of pro-apoptotic pathways, of which Fas-mediated apoptosis is the most prominent.42 T lymphocytes constitutively express Fas receptors, but the Fas ligand (FasL) is expressed only after repeated exposure to antigen or after nonspecific stimulation via the CD3/TCR complex.43,44 Ligation of Fas by FasL results in so called activation-induced cell death (AICD).42 A study of patients with chronic hematologic autoimmunity (having AIHA and/or ITP) showed a defective Fas-mediated AICD in 25% of these patients, which was not explained by reduced Fas expression, FasL function or Fas mutations.45 However, another study was unable to find any defects in Fas function in patients with chronic ITP.46 Fas-mediated AICD in mature T cells is controlled by IL-2, which primes activated T cells to undergo apoptosis via the Fas pathway.47 Disruption of the interaction between the Fas and IL-2 pathways, as in IL-2 refractory cases of AIHA and ITP, will interfere with AICD, leading to expansion of self-reactive T cells that would normally be targeted for elimination.45

Fcγ Receptor Polymorphisms in ITP

As described above, the pathophysiology of ITP is dependent on the recognition of IgG-sensitized platelets by Fcγ receptors (FcγR) on macrophages in the spleen and liver. So far, three classes of Fcγ receptors have been characterized: FcγRI, FcγRII and FcγRIII, where each subclass exists in several different isoforms.48 In humans, 12 FcγR transcripts are involved, all derived from eight genes (Fc γR Ia, Fc γR Ib, Fc γR Ic, Fc γR IIa, Fc γR IIb, Fc γR IIc, Fc γR IIIa and Fc γR IIIb) on chromosome 1.49 FcγRI (CD64) is a high-affinity receptor with the capacity to bind monomeric IgG. FcγRII (CD32) and FcγRIII (CD16) are low-affinity receptors for immune complexes or multimeric IgG. Inherited functional single nucleotide polymorphisms in FcγRIIa and FcγRIIIa results in increased heterogeneity and randomly distributed allelic variants in populations, which may further vary between ethnic groups.50 For FcγRIIa, the genetic polymorphism is the result of a single nucleotide histidine (H) or arginine (R) substitution at position 131, resulting in a marked increase in the binding affinity for IgG2 to FcγRIIa-131H as compared to FcγRIIa-131R.51 In the same way, the binding affinity for IgG1 and IgG3 differs between FcγRIIIa having valine (V) or phenylalanine (F) at codon 158, where FcγRIIIa-158V has the highest affinity.52 It is of interest to note, that a significant over-representation of the FcγRIIa-131H and FcγRIIIa-158V variants were found in children with acute or chronic ITP.53 However, another study of children with chronic ITP failed to find an association between FcγRIIa genotype and disease incidence, but confirmed that the FcγRIIIa-158V variant was increased.54 A similar finding was also reported in adults with chronic ITP.55

Erythrocyte CD47 and Autoimmune Hemolytic Anemia

CD47 (Integrin-associated protein/IAP) is a ubiquitously expressed cell surface glycoprotein, which maps to chromosome 3q13.1-q13.2 in humans and to chromosome 16 in mice.56,57 It was first identified as a protein associated with αvβ3 integrins in placenta and in neutrophil granulocytes, and shown to regulate integrin function and leukocyte reponses to RGD-containing extracellular matrix proteins.58,59 Erythrocytes do not express integrins, but still express high levels of CD47, which suggests important integrin-independent functions for CD47 in these cells. Interestingly, CD47 can function as a ligand for the inhibitory macrophage receptor Signal Regulatory Protein alpha (SIRPα/SHPS-1/BIT/P84).60 This interaction was recently found to be important to prevent phagocytosis of circulating erythrocytes by splenic macrophages, since erythrocytes from CD47-deficient mice were rapidly cleared from the circulation of wild-type recipient mice.61 Clearance of CD47 deficient erythrocytes was not dependent on complement activation, lymphocytes or antibodies, but entirely due to the absence of inhibitory CD47/SIRPα signaling.61 Using CD47-deficient and CD47 wild-type erythrocytes, it was also shown that erythrocyte CD47 can reduce clearance and phagocytosis of IgG opsonized erythrocytes through interaction with macrophage SIRPα.62 In this system, the inhibitory signal generated by CD47/SIRPα interaction is integrated with the prophagocytic Fcγ receptor signal proximal to the decision to phagocytose. Neither the SIRPα nor the Fcγ receptor signal seems to be dominant, rather the activation of phagocytosis is determined by the relative signaling strength of activating and inhibitory signals. In the same way, erythrocytes opsonized with the complement fragment C3bi are bound and phagocytosed via complement receptors (CR3/αMβ2 integrin),63 and also complement-mediated phagocytosis of erythrocytes is regulated by the inhibitory CD47-SIRPα signal.62 As mentioned earlier, Fcγ and complement receptors are known to act synergistically in stimulating phagocytosis of erythrocytes in AIHA. Therefore, it seems likely that phagocytosis of erythrocytes in AIHA is also based on the summation of the prophagocytic signals from Fcγ receptors and complement receptors with the negative signal from SIRPα (fig.3). A significant importance of the inhibitory CD47/SIRPa system in limiting erythrocyte destruction and severity of AIHA is emphasized by studies in the autoimmune-prone nonobese diabetic (NOD) mice. NOD mice that do not develop diabetes, may instead develop a mild form of AIHA at the age of 300-550 days.64 When breeding CD47-deficient NOD mice, we found that a majority of these mice developed an acute lethal form of AIHA at the age of 180-280 days.65 The exact ethiology behind the increased sensitivity of CD47-deficient NOD mice to develop this severe form of AIHA is not entirely clear. However, our recent results suggest that CD47-deficient erythrocytes are more susceptible to autoantibody-mediated immune destruction, since the absent interaction between CD47 and SIRPa enhances pro-phagocytic signals induced by Fcγ and complement receptors.62 CD47-deficient NOD mice all have higher levels of antibody-opsonized erythrocytes than wild-type NOD mice of the same age. It is therefore suggested that the onset of anti-erythrocyte autoantibody production is accelerated in CD47-deficient NOD mice, which might be explained by the fact that phagocytosis of CD47-deficient erythrocytes occure already at very low levels of IgG opsonization, which may possibly promote antigen presentation of pathogenic self-peptides. In a more generalized perspective, during microbial infections, the inhibitory CD47/SIRPα interaction may be of importance to avoid autoimmune cellular damages to host cells by nonspecifically and transiently induced autoantibodies. Here, a low level of IgG opsonization might be enough to trigger phagocytosis of a foreign particle that do not express CD47, whereas a host cell, such as an erythrocyte, would not be phagocytosed due to its expression of CD47 and the resulting inhibitory signals generated upon contact with macrophage SIRPα. However, in autoimmune diseases such as AIHA, elevated erythrocyte IgG opsonization and Fcγ receptor activation will override the CD47-SIRPα signal, resulting in erythrocyte phagocytosis and clinically overt AIHA. Platelets do also express CD47 and investigations are underway to determine the role of inhibitory CD47/SIRPa signaling in the regulation of platelet clearance in ITP.

Figure 3. FcγR and CR-mediated erythrophagocytosis can be down-regulated by CD47/SIRPα interaction.

Figure 3

FcγR and CR-mediated erythrophagocytosis can be down-regulated by CD47/SIRPα interaction. The phagocytosis stimulating signals generated through ligation of FcγR and/or CR are counteracted by the inhibitory receptor SIRPα (more...)


Supported by grants from the Swedish Research Council for Medicine (06P-14098, 31X-14286), the NIH (GM57573-06), the Swedish Society of Medicine, the Åke Wiberg Foundation and the Faculty of Medicine, Umeå University.


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Bookshelf ID: NBK6032


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