Acta Paediatrica Japonica Official Journal of The Japan Pediatric Society
Vol. 34 No. 4 August 1992 (Acta Paediatr Jpn 1992; 34: 385
- 392)
Invited Paper
Primary Immunodeficiency Diseases and Epstein-Barr Virus-induced Lymphoproliferative Disorders Motohiko Okano, M.D., Ph.D., Masanori Nakanishi, M.D., Yuichi Taguchi, M.D., Yukio Sakiyama, M.D., Ph.D. and Shuzo Matsumoto, M.D., Ph.D. Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan
Increased incidence of malignant disorders is noted in patients with both primary and acquired immunodeficiency diseases. The pathogenetic mechanism(s) for these disorders remain unclear. Defective immunosurveillance of these patients, however, is mainly postulated to be responsible for the increased risk of these malignant disorders. Of the malignant disorders, Epstein-Barr virus (EBV)-induced lymphoproliferativedisorders (LPD) have been increasingly reported, possibly due to improved therapeutic management techniques such as bone marrow transplantation, which results in prolonged survival periods for the primary immunodeficiency; the dramatic development of immunosuppressive treatments for transplant recipients; and the growing numbers of acquired immunodeficiency syndrome (AIDS) patients. This review focuses on the primary immunodeficiency diseases and EBV-induced LPD, and discusses pathogenetic mechanism(s) for the increased incidence of these malignant disorders. Key Words Epstein-Barr virus-induced lymphoproliferativedisorders, Primary immunodeficiencydisease
Introduction The Epstein-Barr virus (EBV) was primarily discovered from cultured Burkitt’s lymphoma (BL) cells [l]. This virus is now one of the six Accepted December 20, 1991 Correspondence address: Motohiko Okano, M.D., Ph.D., Department of Pediatrics, Kitami Red Cross Hospital, North 6 East 2, Kitami 090, Japan.
known human herpesviruses, and like others excluding varicella-zoster virus, a primary infection of EBV is generally subclinical. In mostly adolescents and young adults, a primary infection of EBV, however, leads to an overt clinical disease such as infectious mononucleosis (IM). The causative relationship between EBV and BL remains unclear. Nevertheless, almost all patients with BL have high antibody titers to EBV and tumors contain the viral genome.
386 (2) Okano et al.
Similar observations were also noted in patients with undifferentiated nasopharyngeal carcinoma (NPC), which is highly endemic in SouthEast Asia and China. These various EBVassociated diseases are thought to be caused chiefly by different individuals’ immunocompetence, as well as by unknown environmental and genetic factors. Control of EBV infection in vivo is mediated primarily by EBV-specific cytotoxic T cells (CTL) and by specific antibodies directed against virally-determined antigens [ 11. Antibody-dependent cell-mediated cytotoxicity (ADCC) and augmented natural killer (NK) cell activity may play accessory roles. An upset of the delicate balance between the virus-infected cells and host defenses results in a broad spectrum of abnormal lymphoid proliferation among immunologically compromised patients. Furthermore, recent advances in the treatment of patients with primary immunodeficiency diseases, including bone marrow transplantation (which induces a more profound immunodeficient status by the use of immunosuppressive drugs). and the growing numbers of recipients with bone marrow transplantation (and other organ transplantation) and acquired immunodeficiency syndrome (AIDS) result in increased numbers of EBV-induced lymphoproliferative disorders (LPD) [ 1,2]. However. pathogenetic mechanism(s) have not been fully characterized. Under normal circumstances, the antibody response to EBV is tightly regulated by the host immune systems [I]. Therefore, the serological profiles of healthy individuals are relatively stable. whereas patients with various immunodeficiency disorders show abnormal EBV serological profiles. In the majority of such cases. elevated IgG antibody titers of anti-EBV viral capsid antigen (VCA), anti-early antigen (EA)diffuse (D). or anti-EA-restricted (R) are observed. The absence of IgG antibody to EBVdetermined nuclear antigen (EBNA) has been noted in some patients with T cell dysfunction. Additionally, some patients with primary immunodeficiency disease who lack immunoglobulin production and patients with EBV-seronegative X-linked lymphoproliferative syndrome (XLP)
receive monthly immunoglobulin replacement therapy to protect against severe infection [3,4]. In these patients, accurate serodiagnosis of EBV infection becomes problematic when EBVspecific antibodies from exogenous immunoglobulin are present in the sera. This review focuses on EBV-induced LPD in patients with primary immunodeficiency diseases in an attempt to recognize the possible pathogenetic mechanism(s) of these diseases. The computer literature search program MEDLINE and Index Medicus were utilized using the following key words: primary immunodeficiency, EBV, lymphoma, lymphoproliferative disorder and IM. The titles of prominent textbooks were also checked for these headings. The search covered material published between 1960 and 199 1. In addition to the literature, this review examines 17 Japanese patients with primary immunodeficiencies whom we have recently studied and their relationship to EBV, including 14 patients with ataxia telangiectasia (AT) and three patients with Wiskott-Aldrich syndrome (WAS).
Features of EBV-induced LPD in Primary Immunodeficiency Diseases Reported cases are summarized in Table 1. To date. 12 well-characterized cases of EBVinduced LPD in patients with primary immunodeficiency diseases have been reported in the English literature. Additionally, XLP characterized by an unusual response to EBV infection resulting in severe or fatal IM, malignant lymphoma and/or hypogammaglobulinemia [ 51, will be discussed separately.
Ataxia Telangiectasia Ataxia telangiectasia (AT) is characterized by progressive ataxia, oculocutaneous telangiectasia and recurrent sinopulmonary infections [3]. Raised levels of serum a-fetoprotein, decreased levels of IgA, IgE, IgG4 and often IgG2 were demonstrated. AT is an autosomal recessive trait. A high frequency of malignant diseases is well known, including epithelial cell, gastric and lymphoreticular malignancies [2]. The increased
Acta Paediatr Jpn
Primary immunodeficiency and EBV infection ( 3 ) 387 Table 1. Reported Epstein-Barr virus-induced lymphoproliferative disorders in primary immunodeficiency diseases Patient 1
2 3 4 5 6
I 8 9
Age (years)
Sex
9 5 14
M F M M M F M M M
12 11 10 1 12
2
1 F 3 months F 12 8 months F *Following bone marrow
10 11
Disease
Pathological findings
Ataxia telangiectasia Malignant lymphoma Dysgammaglobulinemia Immunoblastic sarcoma Wiskott-Aldrich syndrome Immunoblastic sarcoma Severe combined immunodeficiency Malignant lymphoma* Ataxia telangiectasia Malignant lymphoma Ataxia telangiectasia Malignant lymphoma Severe combined immunodeficiency Malignant’lymphoma* Wiskott-Aldrich syndrome Ly mphoproliferation** Wiskott-Aldrich Syndrome Lymphoproliferation* Combined immunodeficiency Lymphoproliferation* Severe combined immunodeficiency Lymphoproliferation Severe combined immunodeficiency Lymphoproliferation* transplantation; **lymphomatoid granulomatosis.
incidence of chromosomal breakage and cytogenetic rearrangement are linked with the evolution of clone cells that are thought to be premalignant. Joncas et al. (1977) first described the high prevalence of antibodies to EA, indicating the presence of active EBV infection in patients with AT [6]. Three cases of malignant lymphoma have been histopathologically reported. First, Saemundsen et al. (1981) reported an undifferentiated lymphoma of the mesenteric lymph node in a 9 year old Caucasian boy [7]. Subsequently, we have reported two cases of malignant lymphoma among 14 patients with Japanese AT [8]. The first case was an 11 year old boy. EBNApositive blast cells were present in his peripheral blood at 2-3% for years, and high IgG antibody titers to VCA and EA-(D) associated with low antibody titers to EBNA were noted. A nasopharyngeal tumor developed, and histopathology demonstrated a poorly differentiated nonHodgkin’s lymphoma, in which EBNA and EBV DNA were not significantly detected. The second patient was a 10 year old Japanese girl. High EA and VCA IgG antibody titers and low EBNA antibody titers were noted. EBNA-positive cells ( 1-2%) had been detected in her peripheral blood. LPD occurred at the cervical lymph node and demonstrated diffuse large cell lymphoma. EBNA-positive tumor cells expressed the IgD heavy chain and lambda light chain. Additionally, the other 11 seropositive patients had also high IgG antibody titers to
Vol. 34 No. 4 August 1992
Year
Reference
1981 1981 1984 1985 1986 1986 1986 1986 1988 1988 1990 1990
19 10 16 8 8 17 12 13 13 18 18
I
VCA.and EA, with a low or normal antibody response to EBNA. EBV-related serological profiles in 14 patients with Japanese AT are shown in Table 2. In addition to the chromosomal instability, patients with AT have B and T cells that are defective in function and number. Defective immunosurveillance, chromosomal instability and viral infection may underlie the development of LPD.
Wiskott-Aldrich Syndrome This syndrome is characterized by recurrent infections, eczema and thrombocytopenia [3]. The platelets are small, and the surface glycoprotein sialophorin antigen (CD43), which appears to be responsible for stabilizing the cell membrane, is commonly unstable in the membranes of leukocytes and platelets. Serum immunoglobulins may at first be normal, but a progressive decrease of IgM initially develops. Progressive lymphopenia, most markedly in the T lymphocytes series, develops. As was shown in patients with AT, high IgG antibody titers to VCA and EA are noted [9]. Additionally, two of three Japanese patients with Wiskott-Aldrich syndrome (WAS) were seropositive and had similar EBV antibody patterns [lo]. Three patients of EBV-induced LPD were reported in the literature. The first patient was a 14 year old Japanese boy who showed high IgG antibody titers to VCA and EA [lo]. IgM and IgA antibodies to VCA had also been positive, while low IgG antibody titers to EBNA were noted. He had
388 (4) Okano et a1 Table 2. Epstein-Barr virus antibodies in Japanese patients with ataxia telangiectasia Patient
Age (years)
Sex
I
16 6 3 13
F M
-7
3
4
5
6 7 8 9 10 11
12 13 14
12 10 17
F F F F M
13
M
6
F F F
4
8 3 10
9
M F F
VCA-lgG
VCA-lgM
2560 2560 640
1 5
1280
1 5
Vol. 34 No. 4 August 1992 (Acta Paediatr Jpn 1992; 34: 385
- 392)
Invited Paper
Primary Immunodeficiency Diseases and Epstein-Barr Virus-induced Lymphoproliferative Disorders Motohiko Okano, M.D., Ph.D., Masanori Nakanishi, M.D., Yuichi Taguchi, M.D., Yukio Sakiyama, M.D., Ph.D. and Shuzo Matsumoto, M.D., Ph.D. Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan
Increased incidence of malignant disorders is noted in patients with both primary and acquired immunodeficiency diseases. The pathogenetic mechanism(s) for these disorders remain unclear. Defective immunosurveillance of these patients, however, is mainly postulated to be responsible for the increased risk of these malignant disorders. Of the malignant disorders, Epstein-Barr virus (EBV)-induced lymphoproliferativedisorders (LPD) have been increasingly reported, possibly due to improved therapeutic management techniques such as bone marrow transplantation, which results in prolonged survival periods for the primary immunodeficiency; the dramatic development of immunosuppressive treatments for transplant recipients; and the growing numbers of acquired immunodeficiency syndrome (AIDS) patients. This review focuses on the primary immunodeficiency diseases and EBV-induced LPD, and discusses pathogenetic mechanism(s) for the increased incidence of these malignant disorders. Key Words Epstein-Barr virus-induced lymphoproliferativedisorders, Primary immunodeficiencydisease
Introduction The Epstein-Barr virus (EBV) was primarily discovered from cultured Burkitt’s lymphoma (BL) cells [l]. This virus is now one of the six Accepted December 20, 1991 Correspondence address: Motohiko Okano, M.D., Ph.D., Department of Pediatrics, Kitami Red Cross Hospital, North 6 East 2, Kitami 090, Japan.
known human herpesviruses, and like others excluding varicella-zoster virus, a primary infection of EBV is generally subclinical. In mostly adolescents and young adults, a primary infection of EBV, however, leads to an overt clinical disease such as infectious mononucleosis (IM). The causative relationship between EBV and BL remains unclear. Nevertheless, almost all patients with BL have high antibody titers to EBV and tumors contain the viral genome.
386 (2) Okano et al.
Similar observations were also noted in patients with undifferentiated nasopharyngeal carcinoma (NPC), which is highly endemic in SouthEast Asia and China. These various EBVassociated diseases are thought to be caused chiefly by different individuals’ immunocompetence, as well as by unknown environmental and genetic factors. Control of EBV infection in vivo is mediated primarily by EBV-specific cytotoxic T cells (CTL) and by specific antibodies directed against virally-determined antigens [ 11. Antibody-dependent cell-mediated cytotoxicity (ADCC) and augmented natural killer (NK) cell activity may play accessory roles. An upset of the delicate balance between the virus-infected cells and host defenses results in a broad spectrum of abnormal lymphoid proliferation among immunologically compromised patients. Furthermore, recent advances in the treatment of patients with primary immunodeficiency diseases, including bone marrow transplantation (which induces a more profound immunodeficient status by the use of immunosuppressive drugs). and the growing numbers of recipients with bone marrow transplantation (and other organ transplantation) and acquired immunodeficiency syndrome (AIDS) result in increased numbers of EBV-induced lymphoproliferative disorders (LPD) [ 1,2]. However. pathogenetic mechanism(s) have not been fully characterized. Under normal circumstances, the antibody response to EBV is tightly regulated by the host immune systems [I]. Therefore, the serological profiles of healthy individuals are relatively stable. whereas patients with various immunodeficiency disorders show abnormal EBV serological profiles. In the majority of such cases. elevated IgG antibody titers of anti-EBV viral capsid antigen (VCA), anti-early antigen (EA)diffuse (D). or anti-EA-restricted (R) are observed. The absence of IgG antibody to EBVdetermined nuclear antigen (EBNA) has been noted in some patients with T cell dysfunction. Additionally, some patients with primary immunodeficiency disease who lack immunoglobulin production and patients with EBV-seronegative X-linked lymphoproliferative syndrome (XLP)
receive monthly immunoglobulin replacement therapy to protect against severe infection [3,4]. In these patients, accurate serodiagnosis of EBV infection becomes problematic when EBVspecific antibodies from exogenous immunoglobulin are present in the sera. This review focuses on EBV-induced LPD in patients with primary immunodeficiency diseases in an attempt to recognize the possible pathogenetic mechanism(s) of these diseases. The computer literature search program MEDLINE and Index Medicus were utilized using the following key words: primary immunodeficiency, EBV, lymphoma, lymphoproliferative disorder and IM. The titles of prominent textbooks were also checked for these headings. The search covered material published between 1960 and 199 1. In addition to the literature, this review examines 17 Japanese patients with primary immunodeficiencies whom we have recently studied and their relationship to EBV, including 14 patients with ataxia telangiectasia (AT) and three patients with Wiskott-Aldrich syndrome (WAS).
Features of EBV-induced LPD in Primary Immunodeficiency Diseases Reported cases are summarized in Table 1. To date. 12 well-characterized cases of EBVinduced LPD in patients with primary immunodeficiency diseases have been reported in the English literature. Additionally, XLP characterized by an unusual response to EBV infection resulting in severe or fatal IM, malignant lymphoma and/or hypogammaglobulinemia [ 51, will be discussed separately.
Ataxia Telangiectasia Ataxia telangiectasia (AT) is characterized by progressive ataxia, oculocutaneous telangiectasia and recurrent sinopulmonary infections [3]. Raised levels of serum a-fetoprotein, decreased levels of IgA, IgE, IgG4 and often IgG2 were demonstrated. AT is an autosomal recessive trait. A high frequency of malignant diseases is well known, including epithelial cell, gastric and lymphoreticular malignancies [2]. The increased
Acta Paediatr Jpn
Primary immunodeficiency and EBV infection ( 3 ) 387 Table 1. Reported Epstein-Barr virus-induced lymphoproliferative disorders in primary immunodeficiency diseases Patient 1
2 3 4 5 6
I 8 9
Age (years)
Sex
9 5 14
M F M M M F M M M
12 11 10 1 12
2
1 F 3 months F 12 8 months F *Following bone marrow
10 11
Disease
Pathological findings
Ataxia telangiectasia Malignant lymphoma Dysgammaglobulinemia Immunoblastic sarcoma Wiskott-Aldrich syndrome Immunoblastic sarcoma Severe combined immunodeficiency Malignant lymphoma* Ataxia telangiectasia Malignant lymphoma Ataxia telangiectasia Malignant lymphoma Severe combined immunodeficiency Malignant’lymphoma* Wiskott-Aldrich syndrome Ly mphoproliferation** Wiskott-Aldrich Syndrome Lymphoproliferation* Combined immunodeficiency Lymphoproliferation* Severe combined immunodeficiency Lymphoproliferation Severe combined immunodeficiency Lymphoproliferation* transplantation; **lymphomatoid granulomatosis.
incidence of chromosomal breakage and cytogenetic rearrangement are linked with the evolution of clone cells that are thought to be premalignant. Joncas et al. (1977) first described the high prevalence of antibodies to EA, indicating the presence of active EBV infection in patients with AT [6]. Three cases of malignant lymphoma have been histopathologically reported. First, Saemundsen et al. (1981) reported an undifferentiated lymphoma of the mesenteric lymph node in a 9 year old Caucasian boy [7]. Subsequently, we have reported two cases of malignant lymphoma among 14 patients with Japanese AT [8]. The first case was an 11 year old boy. EBNApositive blast cells were present in his peripheral blood at 2-3% for years, and high IgG antibody titers to VCA and EA-(D) associated with low antibody titers to EBNA were noted. A nasopharyngeal tumor developed, and histopathology demonstrated a poorly differentiated nonHodgkin’s lymphoma, in which EBNA and EBV DNA were not significantly detected. The second patient was a 10 year old Japanese girl. High EA and VCA IgG antibody titers and low EBNA antibody titers were noted. EBNA-positive cells ( 1-2%) had been detected in her peripheral blood. LPD occurred at the cervical lymph node and demonstrated diffuse large cell lymphoma. EBNA-positive tumor cells expressed the IgD heavy chain and lambda light chain. Additionally, the other 11 seropositive patients had also high IgG antibody titers to
Vol. 34 No. 4 August 1992
Year
Reference
1981 1981 1984 1985 1986 1986 1986 1986 1988 1988 1990 1990
19 10 16 8 8 17 12 13 13 18 18
I
VCA.and EA, with a low or normal antibody response to EBNA. EBV-related serological profiles in 14 patients with Japanese AT are shown in Table 2. In addition to the chromosomal instability, patients with AT have B and T cells that are defective in function and number. Defective immunosurveillance, chromosomal instability and viral infection may underlie the development of LPD.
Wiskott-Aldrich Syndrome This syndrome is characterized by recurrent infections, eczema and thrombocytopenia [3]. The platelets are small, and the surface glycoprotein sialophorin antigen (CD43), which appears to be responsible for stabilizing the cell membrane, is commonly unstable in the membranes of leukocytes and platelets. Serum immunoglobulins may at first be normal, but a progressive decrease of IgM initially develops. Progressive lymphopenia, most markedly in the T lymphocytes series, develops. As was shown in patients with AT, high IgG antibody titers to VCA and EA are noted [9]. Additionally, two of three Japanese patients with Wiskott-Aldrich syndrome (WAS) were seropositive and had similar EBV antibody patterns [lo]. Three patients of EBV-induced LPD were reported in the literature. The first patient was a 14 year old Japanese boy who showed high IgG antibody titers to VCA and EA [lo]. IgM and IgA antibodies to VCA had also been positive, while low IgG antibody titers to EBNA were noted. He had
388 (4) Okano et a1 Table 2. Epstein-Barr virus antibodies in Japanese patients with ataxia telangiectasia Patient
Age (years)
Sex
I
16 6 3 13
F M
-7
3
4
5
6 7 8 9 10 11
12 13 14
12 10 17
F F F F M
13
M
6
F F F
4
8 3 10
9
M F F
VCA-lgG
VCA-lgM
2560 2560 640
1 5
1280
1 5
