Draz MY Egypt COMMON VARIABLE IMMUNODEFICIENCYP,PID,HYPOGAMMAGLOBULINEMIA

الرحيم الرحمن الله الرحيم بسم الرحمن الله بسم

Review of genetic aspect and recent advances Review of genetic aspect and recent advances in common variable immunodeficiency as a in common variable immunodeficiency as a

main cause of hypogammaglobulinemia.main cause of hypogammaglobulinemia.

An essay byAn essay by

DR/Rehab Mohammed LepshteenDR/Rehab Mohammed Lepshteen

DR/MAHMOOD YASEENDR/MAHMOOD YASEEN

ContentsContents

Chapter I: Primary immunodeficiency.Chapter I: Primary immunodeficiency.

Chapter II: Primary Chapter II: Primary hypogammaglobulinemia.hypogammaglobulinemia.

Chapter III: Common variable Chapter III: Common variable immunodeficiency.immunodeficiency.

Primary immunodeficiency diseasesPrimary immunodeficiency diseases

Primary immunodeficiency diseases (PIDs) are a Primary immunodeficiency diseases (PIDs) are a class of disorders in which there is an intrinsic class of disorders in which there is an intrinsic defect in the human immune system. defect in the human immune system.

PIDs predispose affected individuals to increased PIDs predispose affected individuals to increased rate and severity of infection, immune rate and severity of infection, immune dysregulation with autoimmune disease, and dysregulation with autoimmune disease, and malignancy .malignancy .

The incidence for all PIDs together ranges from 1 / The incidence for all PIDs together ranges from 1 / 2,000 to 1 / 10,000 live births2,000 to 1 / 10,000 live births

• Primary immunodeficiency diseases are classified according to the affected Primary immunodeficiency diseases are classified according to the affected limb of immune system into:limb of immune system into:

a) Defects in innate immunity:a) Defects in innate immunity: i) Phagocytic dysfunction .i) Phagocytic dysfunction . ii) Complement deficiencies. ii) Complement deficiencies. b) Defects in adaptive immunity:b) Defects in adaptive immunity: i) Humoral immune deficiency.i) Humoral immune deficiency. ii ) Cellular immune deficiency.ii ) Cellular immune deficiency.iii) Combined immunodeficiency .iii) Combined immunodeficiency .

• Geha et al.,2007 summarized the classification of adaptive PIDs according to Geha et al.,2007 summarized the classification of adaptive PIDs according to the last Committee of the International Union of Immunological Societies the last Committee of the International Union of Immunological Societies (IUIS) as follows :(IUIS) as follows :

A –T and B cell immunodeficiencies that include:A –T and B cell immunodeficiencies that include:

B- Predominantly antibody deficienciesB- Predominantly antibody deficiencies

C- Other well-defined immunodeficiency syndromesC- Other well-defined immunodeficiency syndromes

Etiology of PIDs:Etiology of PIDs:• Primary immunodeficiency diseases are heritable Primary immunodeficiency diseases are heritable

disorders of immune system function. disorders of immune system function.

• Many are associated with single gene defects, Many are associated with single gene defects, whereas others may be polygenic .whereas others may be polygenic .

Complications of PIDs:Complications of PIDs:• PIDs cause increased susceptibility to infection, PIDs cause increased susceptibility to infection,

autoimmune disease, and malignancyautoimmune disease, and malignancy

Diagnosis of PIDs :Diagnosis of PIDs :• Laboratory testing for the diagnosis of PIDs can be a Laboratory testing for the diagnosis of PIDs can be a time intensivetime intensive and and

expensiveexpensive . . • There are There are four levels of laboratory testingfour levels of laboratory testing for diagnosis of PIDs (Schroeder, for diagnosis of PIDs (Schroeder,

2007). 2007). • Jayabal , 2007 summarized the tests to detect immunodeficiency according to Jayabal , 2007 summarized the tests to detect immunodeficiency according to

the suspected causes of immunodeficiency as follows:the suspected causes of immunodeficiency as follows:

1- Complete blood count and differential.1- Complete blood count and differential.2- Quantitative serum Ig analysis by rate nephlometry .2- Quantitative serum Ig analysis by rate nephlometry .3- Antibody response tests by testing the Antibody response to 3- Antibody response tests by testing the Antibody response to

pneumococcal ,tetanus, and diphtheria intramuscular vaccination. Also, cell pneumococcal ,tetanus, and diphtheria intramuscular vaccination. Also, cell mediated immunity testing by Candida and tetanus skin response tests .mediated immunity testing by Candida and tetanus skin response tests .

4- Immunoglobulin G subclass analysis.4- Immunoglobulin G subclass analysis.5- B and T cell number .5- B and T cell number .6- Lymphocyte surface markers e.g. CD3, CD4 ,CD8 ,CD19 .6- Lymphocyte surface markers e.g. CD3, CD4 ,CD8 ,CD19 .7- Phagocyte function studies of monocytes and neutrophils. 7- Phagocyte function studies of monocytes and neutrophils. 8- Natural killer cytotoxicity studies.8- Natural killer cytotoxicity studies.9- 9- Complement screening of C3,C4,CH50.Complement screening of C3,C4,CH50.10-Enzymes assay of adenosine deaminase , and purine nucleotide phosphorylase.10-Enzymes assay of adenosine deaminase , and purine nucleotide phosphorylase.11-Biopsies from bone marrow, lymph nodes ,skin ,thymus ,and rectum according 11-Biopsies from bone marrow, lymph nodes ,skin ,thymus ,and rectum according

to suspected causes.to suspected causes.12- Familial and genetic studies.12- Familial and genetic studies.

Lines of treatment of PIDsLines of treatment of PIDs

The four principal general categories of therapy include:The four principal general categories of therapy include:

1-Bone marrow and hematopoietic stem cell transplantation1-Bone marrow and hematopoietic stem cell transplantation : :

hematopoietic stem cell transplantation (HSCT) is a very effective treatment for many of hematopoietic stem cell transplantation (HSCT) is a very effective treatment for many of PIDs . The initial successful application of stem cell transplantation in 1968 in two patients PIDs . The initial successful application of stem cell transplantation in 1968 in two patients with Sever combined immuno-deficiency (SCID )gave evidence that a new donor derived with Sever combined immuno-deficiency (SCID )gave evidence that a new donor derived immune system can reverse the poor prognosis in many PIDs . immune system can reverse the poor prognosis in many PIDs .

2-Gene therapy:2-Gene therapy: The first true success of human gene therapy was reported with the correction of several The first true success of human gene therapy was reported with the correction of several patients with X-linked SCID by ex vivo transduction and reinfusion of stem cells with a patients with X-linked SCID by ex vivo transduction and reinfusion of stem cells with a functional copy of the gamma chain gene by using a retroviral vector (Bonilla and functional copy of the gamma chain gene by using a retroviral vector (Bonilla and Geha .,2003). Now, all gene therapy using retroviral vectors for immunodeficiency are Geha .,2003). Now, all gene therapy using retroviral vectors for immunodeficiency are freezed after the occurrence of T cell leukemia in two of the 10 children administered gene freezed after the occurrence of T cell leukemia in two of the 10 children administered gene therapy for SCID with therapy for SCID with IL2RGIL2RG gene mutation. It was found that the retroviral gene gene mutation. It was found that the retroviral gene construct of the construct of the IL2RGIL2RG gene inserted itself on the oncogene gene inserted itself on the oncogene LMO2LMO2 that is aberrantly that is aberrantly expressed in acute lymphocytic leukemia of childhood. Thus, insertional oncogenesis was expressed in acute lymphocytic leukemia of childhood. Thus, insertional oncogenesis was the probable cause of the T-cell leukemia in these two cases .the probable cause of the T-cell leukemia in these two cases .

Lines of treatment of PIDsLines of treatment of PIDs

3-Intravenous Igs (IVIG) and subcutaneous Igs (SCIG):3-Intravenous Igs (IVIG) and subcutaneous Igs (SCIG):

Immunoglobulin replacement therapy is now the standard therapy for Immunoglobulin replacement therapy is now the standard therapy for most antibody deficiencies. The half-life of IgG is approximately 21 most antibody deficiencies. The half-life of IgG is approximately 21 days, and standard replacement doses of 400–600 mg/kg given every days, and standard replacement doses of 400–600 mg/kg given every 3-4 weeks are usually a sufficient replacement . The regular injections 3-4 weeks are usually a sufficient replacement . The regular injections of Igs reduces the annual incidence of infections from 12.4% to 3.2%. of Igs reduces the annual incidence of infections from 12.4% to 3.2%. Immunoglobulin replacement can be given by subcutaneous Immunoglobulin replacement can be given by subcutaneous injection , but Intramuscular immunoglobulins does not have a role in injection , but Intramuscular immunoglobulins does not have a role in the management of immunoglobulin deficiency .the management of immunoglobulin deficiency .

4- Anti-microbial prophylaxis and treatment4- Anti-microbial prophylaxis and treatment (Bonilla et al., 2005). (Bonilla et al., 2005).

PrognosisPrognosis

Certain severe PIDs e.g., SCID become apparent early in life, with only a short Certain severe PIDs e.g., SCID become apparent early in life, with only a short asymptomatic period after birth. Without an effective early intervention, the asymptomatic period after birth. Without an effective early intervention, the majority result in death during the first two years of life . majority result in death during the first two years of life .

Patients with antibody or complement deficiencies can have near normal life Patients with antibody or complement deficiencies can have near normal life spans if their deficiencies are diagnosed early, managed properly, and are not spans if their deficiencies are diagnosed early, managed properly, and are not affected by concurrent chronic diseases. affected by concurrent chronic diseases.

The mortality causes in PIDs patients was due to respiratory infections in 43.8% , The mortality causes in PIDs patients was due to respiratory infections in 43.8% , hematological disorders in 31.3% , GI complications in 9.3%,ENT hematological disorders in 31.3% , GI complications in 9.3%,ENT complications in 9.3% , and CNS complications in 6.3%.complications in 9.3% , and CNS complications in 6.3%.

Primary hypogammaglobulinemiaPrimary hypogammaglobulinemia

• Hypogammaglobulinemia means a low level of any or Hypogammaglobulinemia means a low level of any or all of the immunoglobulins because all of the all of the immunoglobulins because all of the immunoglobulins fall in the category of the serum immunoglobulins fall in the category of the serum gamma globulins . gamma globulins .

• Immunoglobulin deficiencies are a heterogeneous group Immunoglobulin deficiencies are a heterogeneous group of disorders that include :of disorders that include :

I-primary hypogammaglobulinemia where B cells has I-primary hypogammaglobulinemia where B cells has intrinsic defects.intrinsic defects.

II- secondary hypogammaglobulinemia where B cells has II- secondary hypogammaglobulinemia where B cells has normal function but other diseases affect serum normal function but other diseases affect serum antibodies level .antibodies level .

I -The primary hypogammaglobulinemia:I -The primary hypogammaglobulinemia:

• Primary hypogammaglobulinemia is the most common type of Primary hypogammaglobulinemia is the most common type of primary immuno -deficiency, and it accounts together for primary immuno -deficiency, and it accounts together for approximately half of all PIDs.approximately half of all PIDs.

• primary immunoglobulin deficiencies may be due to :primary immunoglobulin deficiencies may be due to :

A – B cell or humoral immunodeficiency:A – B cell or humoral immunodeficiency: The most common primary The most common primary humoral deficiencies are:humoral deficiencies are:

1 - IgA deficiency.1 - IgA deficiency.2 - Common variable immunodeficiency (CVID).2 - Common variable immunodeficiency (CVID).3 - X-linked and autosomal recessive agammaglobulinemias.3 - X-linked and autosomal recessive agammaglobulinemias.4 - Transient hypogammaglobulinemia of infancy. 4 - Transient hypogammaglobulinemia of infancy. 5 - IgG subclass deficiency.5 - IgG subclass deficiency.6 - Specific antibody deficiency. 6 - Specific antibody deficiency. 7 - Hyper-IgM syndrome.7 - Hyper-IgM syndrome.

B- Combined immunodeficiency:B- Combined immunodeficiency: Both humoral and cellular immunity are Both humoral and cellular immunity are impaired. impaired.

C- Specific syndromes accompanied by antibody deficiency :C- Specific syndromes accompanied by antibody deficiency : It It include Wiskott -Aldrich syndrome, and ataxia- telangiectasia .include Wiskott -Aldrich syndrome, and ataxia- telangiectasia .

II-Secondary hypogammaglobulinemia:II-Secondary hypogammaglobulinemia:

Secondary hypogammaglobulinemia occurs due to a variety of Secondary hypogammaglobulinemia occurs due to a variety of conditions that include :conditions that include :

1-Immunoglobulin loss1-Immunoglobulin loss due to renal or gastrointestinal diseases. due to renal or gastrointestinal diseases.

2-Decreased immunoglobulin production2-Decreased immunoglobulin production due to bone marrow diseases and due to bone marrow diseases and malignancies .malignancies .

3-Medications 3-Medications e.g. antirheumatic drugs such as sulfasalazine and gold, systemic e.g. antirheumatic drugs such as sulfasalazine and gold, systemic steroids, phenytoin, carbamazepine , and androgen replacement therapy.steroids, phenytoin, carbamazepine , and androgen replacement therapy.

4-High-stress states4-High-stress states e.g. during reduced calorie intake, sleep deprivation , and e.g. during reduced calorie intake, sleep deprivation , and extreme physical activity (Rose and Lange, 2006).extreme physical activity (Rose and Lange, 2006).

Common primary hypogammaglobulinemiasCommon primary hypogammaglobulinemiasA – B cell or humoral immunodeficiency:A – B cell or humoral immunodeficiency:

1- Selective IgA deficiency (sIgAD):1- Selective IgA deficiency (sIgAD):

• Selective IgA deficiency (sIgAD) is the most common PID Selective IgA deficiency (sIgAD) is the most common PID in humans. According to estimates based on blood donation in humans. According to estimates based on blood donation analyses, sIgAD incidence is 1 / 300 – 1 / 700 which is the analyses, sIgAD incidence is 1 / 300 – 1 / 700 which is the highest incidence of all PIDs. highest incidence of all PIDs.

• The diagnostic criteria of sIgAD includes any Male or The diagnostic criteria of sIgAD includes any Male or female patient greater than 4 years of age who has a serum female patient greater than 4 years of age who has a serum IgA of less than 7 mg/dl , and normal serum IgG and IgM IgA of less than 7 mg/dl , and normal serum IgG and IgM after exclusion of other causes of after exclusion of other causes of hypogammaglobulinemia . hypogammaglobulinemia .

Common primary hypogammaglobulinemiasCommon primary hypogammaglobulinemiasA – B cell or humoral immunodeficiency:A – B cell or humoral immunodeficiency:

2) 2) X-linked and autosomal recessive agammaglobulinemias:X-linked and autosomal recessive agammaglobulinemias:

• In agammaglobulinemia, there is sever decrease in B cells count and serum In agammaglobulinemia, there is sever decrease in B cells count and serum immunoglobulin levels. The causes of agammaglobulinemias are :immunoglobulin levels. The causes of agammaglobulinemias are :

a- X-linked Burton's agammaglobulinemia: Due to Burton's tyrosine kinase a- X-linked Burton's agammaglobulinemia: Due to Burton's tyrosine kinase

(BTK) gene defects.(BTK) gene defects.b- Autosomal recessive agammaglobulinemia with genetic defects in:b- Autosomal recessive agammaglobulinemia with genetic defects in:

• X-linked agammaglobulinemia (XLA) is the most common X-linked agammaglobulinemia (XLA) is the most common disorder of primary agammaglobulinemia as it accounts for 80% disorder of primary agammaglobulinemia as it accounts for 80% to 90% of all cases . In XLA due to mutations of Bruton's tyrosine to 90% of all cases . In XLA due to mutations of Bruton's tyrosine kinase (Btk), there is lack of the enzyme or the generation of a kinase (Btk), there is lack of the enzyme or the generation of a non-functional enzyme leading to disturbance of the signaling non-functional enzyme leading to disturbance of the signaling pathway responsible for the maturation of pro-B cells to mature pathway responsible for the maturation of pro-B cells to mature memory B cells. memory B cells.

3) Transient hypogammaglobulinemia of infancy (THI):3) Transient hypogammaglobulinemia of infancy (THI):

• Transient hypogammaglobulinemia of infancy is a heterogeneous Transient hypogammaglobulinemia of infancy is a heterogeneous disorder characterized by reduced serum IgG levels in early disorder characterized by reduced serum IgG levels in early infancy .infancy .

• Maternal IgG in the infant disappears after birth with a half-life Maternal IgG in the infant disappears after birth with a half-life of 25-30 days, and intrinsic IgG production usually begins of 25-30 days, and intrinsic IgG production usually begins immediately after birth. immediately after birth.

• In transient hypogammaglobulinaemia of infancy, intrinsic In transient hypogammaglobulinaemia of infancy, intrinsic immunoglobulin production is delayed for up to 36 months, immunoglobulin production is delayed for up to 36 months, resulting in low IgG and IgA concentrations , but IgM resulting in low IgG and IgA concentrations , but IgM concentration may be normal or low . concentration may be normal or low .

• In the majority of patients immunoglobulin concentrations In the majority of patients immunoglobulin concentrations normalise between 2 and 4 years of age (Esser,2008).normalise between 2 and 4 years of age (Esser,2008).

4) IgG subclass deficiency (IgGSD):4) IgG subclass deficiency (IgGSD):

• IgG exists as four subclasses i.e. IgG1 normally has the highest IgG exists as four subclasses i.e. IgG1 normally has the highest serum concentration, followed by IgG2, IgG3, and IgG4. serum concentration, followed by IgG2, IgG3, and IgG4.

• Patients may have a normal level of total IgG despite a markedly Patients may have a normal level of total IgG despite a markedly reduced IgG subclass . reduced IgG subclass .

• IgGSD is defined as an abnormally low level of one or more IgG IgGSD is defined as an abnormally low level of one or more IgG subclasses in patients with normal levels of total IgG and IgM.subclasses in patients with normal levels of total IgG and IgM.

• The major clinical association with IgGSD is recurrent Sino The major clinical association with IgGSD is recurrent Sino pulmonary bacterial infection .pulmonary bacterial infection .

5) Specific Antibody Deficiency (SAD):5) Specific Antibody Deficiency (SAD):• SAD is characterized by normal concentrations of IgG, IgA, IgM, and IgG SAD is characterized by normal concentrations of IgG, IgA, IgM, and IgG

subclasses and abnormal IgG antibody responses to polysaccharide vaccines. subclasses and abnormal IgG antibody responses to polysaccharide vaccines.

6) The hyper IgM Syndrome (HIgM):6) The hyper IgM Syndrome (HIgM):

• The hyper-IgM syndrome (HIgM) comprises Inherited defects in class switch The hyper-IgM syndrome (HIgM) comprises Inherited defects in class switch recombination resulting in immunodeficiency . Patients have normal B cell recombination resulting in immunodeficiency . Patients have normal B cell count but low memory B , normal or increased IgM, and low or absent levels of count but low memory B , normal or increased IgM, and low or absent levels of IgA, IgG and IgE(Eley,2008). IgA, IgG and IgE(Eley,2008).

DiseaseDiseaseB cellsB cellsImmunoglobulinsImmunoglobulins

1-Selective IgA.1-Selective IgA.NormalNormalLow IgA ,Normal IgG, IgM.Low IgA ,Normal IgG, IgM.

2-CVID2-CVIDlowlowLow IgG and IgA, Normal/low IgM.Low IgG and IgA, Normal/low IgM.

3-X-linked and autosomal 3-X-linked and autosomal recessive agammaglobulinemias recessive agammaglobulinemias

Absent/lowAbsent/lowLow IgG, IgA , and IgM.Low IgG, IgA , and IgM.

4-Isolated IgG Deficiency.4-Isolated IgG Deficiency.NormalNormalNormalNormal

5-Specific antibody Deficiency.5-Specific antibody Deficiency.NormalNormalNormalNormal

6-HIGM6-HIGMNormalNormalRaised IgM ,Low IgG and IgA.Raised IgM ,Low IgG and IgA.

The pattern of B lymphocytes and immunoglobulin level in various types of The pattern of B lymphocytes and immunoglobulin level in various types of primary hypogammaglobulinemia (Eley , 2008)primary hypogammaglobulinemia (Eley , 2008)..

Common primary hypogammaglobulinemiasCommon primary hypogammaglobulinemiasB- The combined immunodeficienciesB- The combined immunodeficiencies::

• Severe combined immunodeficiencies (SCIDs):Severe combined immunodeficiencies (SCIDs):

• It is a group of genetic disorders characterized by It is a group of genetic disorders characterized by profoundly defective T cell differentiation and B cell profoundly defective T cell differentiation and B cell defects . Most patients die before the end of the second defects . Most patients die before the end of the second year due to infectious complications unless they receive year due to infectious complications unless they receive BMT.BMT.

• SCID is a pediatric emergency. If the diagnosis is made SCID is a pediatric emergency. If the diagnosis is made at birth or shortly thereafter, definitive therapy in the at birth or shortly thereafter, definitive therapy in the form of bone marrow stem cell transplantation can form of bone marrow stem cell transplantation can result in a survival rate as high as 97%, regardless of the result in a survival rate as high as 97%, regardless of the molecular type of SCID . molecular type of SCID .

Common primary hypogammaglobulinemiasCommon primary hypogammaglobulinemiasC- Specific syndromes accompanied by antibody deficiency:C- Specific syndromes accompanied by antibody deficiency:

1- Wiskott-Aldrich syndrome (WAS):1- Wiskott-Aldrich syndrome (WAS):

• The classic WAS triad : thrombocytopenia/small platelets, The classic WAS triad : thrombocytopenia/small platelets, recurrent infections as a result of immunodeficiency, and eczema.recurrent infections as a result of immunodeficiency, and eczema.

• Immunologic abnormalities characteristic for patients with WAS Immunologic abnormalities characteristic for patients with WAS involve both B and T cell function and include defective monocyte involve both B and T cell function and include defective monocyte chemotaxis as well as abnormal morphology of stimulated chemotaxis as well as abnormal morphology of stimulated dendritic cells .dendritic cells .

2-Ataxia-telangiectasia (AT):2-Ataxia-telangiectasia (AT):Ataxia- telangiectasia (AT) is an autosomal recessive inherited Ataxia- telangiectasia (AT) is an autosomal recessive inherited

disease caused by inactivation mutation of the ATM gene. disease caused by inactivation mutation of the ATM gene. It is a multisystemic disease with progressive It is a multisystemic disease with progressive neurologic dysfunctionneurologic dysfunction, ,

especially in the cerebellum, especially in the cerebellum, oculocutaneous telangiectasiaoculocutaneous telangiectasia, , immunodeficiencyimmunodeficiency, recurrent sinopulmonary infections and high , recurrent sinopulmonary infections and high incidence of incidence of neoplasmsneoplasms. .

Laboratory testing of hypogammaglobulinemiaLaboratory testing of hypogammaglobulinemia

A- Specific tests for humoral immune function:A- Specific tests for humoral immune function:

1- Quantitative IgG, IgM, IgA, and IgE.1- Quantitative IgG, IgM, IgA, and IgE.2- IgG subclasses.2- IgG subclasses.3- B cell numbers in peripheral blood (CD19, CD20).3- B cell numbers in peripheral blood (CD19, CD20).4- Measurement of Antibody responses to test immunizations.4- Measurement of Antibody responses to test immunizations.5- In vitro IgG synthesis by mitogen-stimulated purified B cells.5- In vitro IgG synthesis by mitogen-stimulated purified B cells.5- cultured in the presence of anti-CD40 and lymphokines.5- cultured in the presence of anti-CD40 and lymphokines.6- In vitro B cell proliferation with anti-CD40 and IL-4 effect.6- In vitro B cell proliferation with anti-CD40 and IL-4 effect.7- Biopsies: rectal mucosa; lymph nodes (if appropriate).7- Biopsies: rectal mucosa; lymph nodes (if appropriate).8- Molecular and mutation analysis (e.g., Btk, μ heavy chain) 8- Molecular and mutation analysis (e.g., Btk, μ heavy chain)

(Chapel et al.,2007).(Chapel et al.,2007).

• Measurement of Antibody responses to test immunizations includes :Measurement of Antibody responses to test immunizations includes :

1-T cell dependent humoral immune response :1-T cell dependent humoral immune response :

• Tetanus toxoid , diphtheria toxoid, and conjugated pneumococcal Tetanus toxoid , diphtheria toxoid, and conjugated pneumococcal polysaccharidepolysaccharide vaccine are common T cell dependent antigens vaccine are common T cell dependent antigens which is suitable for diagnostic tests of T cell dependant humoral which is suitable for diagnostic tests of T cell dependant humoral immunity. immunity.

• Protective levels of diphtheria and tetanus toxoids are titers greater than Protective levels of diphtheria and tetanus toxoids are titers greater than 0.01IU/ ml. The usual post- immunization response exceeds 1.0 IU/ml or a four 0.01IU/ ml. The usual post- immunization response exceeds 1.0 IU/ml or a four fold rise above pre-immunization level. fold rise above pre-immunization level.

2-T cell independent humoral immune response: 2-T cell independent humoral immune response:

• The T cell independent immune response is measured by using The T cell independent immune response is measured by using the polyvalent unconjugated pneumococcal polysaccharide the polyvalent unconjugated pneumococcal polysaccharide vaccine.vaccine.

• Titers exceeding 2 microgram/ml ,or a four fold rise of post-immunization titers are Titers exceeding 2 microgram/ml ,or a four fold rise of post-immunization titers are considered normal response. considered normal response.

B- Tests for T cell mediated immune function in cases of combined B- Tests for T cell mediated immune function in cases of combined immunodeficiency:immunodeficiency:

1- Absolute lymphocyte count.1- Absolute lymphocyte count.

2- T cell, T subset, and NK cell enumeration (CD3, CD4, CD8; also CD16, CD56).2- T cell, T subset, and NK cell enumeration (CD3, CD4, CD8; also CD16, CD56).

3- Delayed-type hypersensitivity skin tests (only in older children and adults for 3- Delayed-type hypersensitivity skin tests (only in older children and adults for candida, tetanus toxoid, mumps).candida, tetanus toxoid, mumps).

4- In vitro proliferation of lymphocytes to mitogens (PHA, ConA), allogeneic cells, 4- In vitro proliferation of lymphocytes to mitogens (PHA, ConA), allogeneic cells, and specific antigens e.g. candida , tetanus toxoid.and specific antigens e.g. candida , tetanus toxoid.

5- Production of cytokines by activated lymphocytes.5- Production of cytokines by activated lymphocytes.6- Expression of activation markers e.g. CD40L, CD69, and lymphokine receptors 6- Expression of activation markers e.g. CD40L, CD69, and lymphokine receptors

e.g. IL-2 receptor γ chain, IFN-γ receptor after mitogenic stimulation.e.g. IL-2 receptor γ chain, IFN-γ receptor after mitogenic stimulation.7- Enumeration of MHCI and MHCII expressing lymphocytes.7- Enumeration of MHCI and MHCII expressing lymphocytes.8- Chromosome analysis e.g. probe for 22q11.8- Chromosome analysis e.g. probe for 22q11.9- Enzyme assays e.g. ADA, PNP.9- Enzyme assays e.g. ADA, PNP.10- Biopsies: skin, lymph node, and thymus (if appropriate)10- Biopsies: skin, lymph node, and thymus (if appropriate)11- Molecular and mutation analysis e.g., CD40L, γc chain, Jak3, ZAP-70 (Chapel 11- Molecular and mutation analysis e.g., CD40L, γc chain, Jak3, ZAP-70 (Chapel

et al.,2007).et al.,2007).

Common variable immunodeficiencyCommon variable immunodeficiency Definition and incidence:Definition and incidence:• CVID represents a heterogeneous group of immunologic CVID represents a heterogeneous group of immunologic

disorders characterized by low immunoglobulins concentration disorders characterized by low immunoglobulins concentration , defective specific antibody production , and increased , defective specific antibody production , and increased susceptibility to bacterial infection .susceptibility to bacterial infection .

• B cells may be normal or low , and patients often have decreased numbers B cells may be normal or low , and patients often have decreased numbers of switched memory B cells .of switched memory B cells .

• The prevalence has been estimated from 1/10,000 to 1/50,000.The prevalence has been estimated from 1/10,000 to 1/50,000.

HISTORICAL :HISTORICAL :• Janeway et al., 1953Janeway et al., 1953 described the first case associated with CVID. described the first case associated with CVID.

• Cooper et al., 1971Cooper et al., 1971 suggested the name of variable hypogamma -globulinemia due to the variable nature suggested the name of variable hypogamma -globulinemia due to the variable nature of the patients .of the patients .

• Douglas et al., 1974 and Geha et al., 1974Douglas et al., 1974 and Geha et al., 1974 independently was the first to use the name of common independently was the first to use the name of common variable immunodeficiency in a widely published medical journals.variable immunodeficiency in a widely published medical journals.

Classification of CVIDClassification of CVID

• The heterogeneity of common variable immunodeficiency The heterogeneity of common variable immunodeficiency calls for a classification addressing pathogenic calls for a classification addressing pathogenic mechanisms as well as clinical relevance.mechanisms as well as clinical relevance.

• There are 4 classification trials:There are 4 classification trials:

I-Bryant's classification of CVID 1990:I-Bryant's classification of CVID 1990:II- Warnatz's classification of CVID (Freiburg classification,2002 II- Warnatz's classification of CVID (Freiburg classification,2002 III- Piqueras's classification (Paris classification,2003):III- Piqueras's classification (Paris classification,2003):IV-The EUROclass classification,2008: IV-The EUROclass classification,2008:

Classification of CVIDClassification of CVIDI-Bryant's classification of CVID 1990:I-Bryant's classification of CVID 1990:

1-Lack of B lymphocytes1-Lack of B lymphocytes (difficult to differentiate from Briton's agammaglobulin-emia). (difficult to differentiate from Briton's agammaglobulin-emia).2-Decreased B lymphocytic count2-Decreased B lymphocytic count that produce neither IgG nor IgM. that produce neither IgG nor IgM.3-B lymphocytes present3-B lymphocytes present, IgM synthesis active, but IgG synthesis disturbed., IgM synthesis active, but IgG synthesis disturbed.4-Proper B lymphocytic count4-Proper B lymphocytic count, normal IgG and IgM synthesis, but specific antibody , normal IgG and IgM synthesis, but specific antibody

synthesis is disrupted .synthesis is disrupted .

II-Warnatz et al.II-Warnatz et al. classification of CVIDclassification of CVID (Freiburg classification,2002 ) :(Freiburg classification,2002 ) :

1- 1- CVID group ICVID group I that comprises patients with CD27+IgM-IgD- switched memory B cells below that comprises patients with CD27+IgM-IgD- switched memory B cells below 0.4% of total peripheral blood B lymphocytes. Group I can be subdivided according to increased 0.4% of total peripheral blood B lymphocytes. Group I can be subdivided according to increased or normal numbers of CD19+CD21 immature B cells into:or normal numbers of CD19+CD21 immature B cells into:

a) Group Iaa) Group Ia which includes patients with an increased proportion of CD19+CD21- immature B cells. which includes patients with an increased proportion of CD19+CD21- immature B cells. There was significant clustering of patients with splenomegaly and autoimmune cytopenias in There was significant clustering of patients with splenomegaly and autoimmune cytopenias in Group Ia.Group Ia.

b) Group Ibb) Group Ib which includes patients with normal levels of CD19+CD21 immature B cells. which includes patients with normal levels of CD19+CD21 immature B cells.

2- 2- CVID group IICVID group II that includes all patients with normal numbers of CD27+IgM-2IgD- switched that includes all patients with normal numbers of CD27+IgM-2IgD- switched memory B cells (> 0.4%). memory B cells (> 0.4%).

Classification of CVIDClassification of CVID

III-Piqueras et al. classification (Paris classification,2003):III-Piqueras et al. classification (Paris classification,2003):Patients were categorized into three groups:Patients were categorized into three groups: • Group MB0Group MB0 with almost no memory B cells whether switched or non switched. There with almost no memory B cells whether switched or non switched. There

is a higher prevalence of splenomegaly , granulomatous disease, and lymphoid is a higher prevalence of splenomegaly , granulomatous disease, and lymphoid proliferation in group MB0.proliferation in group MB0.

• Group MB1Group MB1 with defective switched memory (IgD-CD27+) but normal non switched with defective switched memory (IgD-CD27+) but normal non switched (IgD+CD27-) memory B cells. A downexpression of activation markers on B cells (IgD+CD27-) memory B cells. A downexpression of activation markers on B cells characterized the group MB1 patients e.g. CD25, CD21, CD80, and CD86. MB1 characterized the group MB1 patients e.g. CD25, CD21, CD80, and CD86. MB1 group was associated with an upexpression of activation markers on T cells e.g. group was associated with an upexpression of activation markers on T cells e.g. HLA-DR, CD95,and CD57 . Splenomegaly was also frequent in group MB1 .HLA-DR, CD95,and CD57 . Splenomegaly was also frequent in group MB1 .

• Group MB2Group MB2 with normal switched (IgD-CD27+) memory B cells. with normal switched (IgD-CD27+) memory B cells.

IV-The EUROclass classification:IV-The EUROclass classification:

• The EUROclass trial was initiated to develop a consensus of two existing The EUROclass trial was initiated to develop a consensus of two existing classification schemes ((Paris and Freiburg ) based on flow cytometric B classification schemes ((Paris and Freiburg ) based on flow cytometric B cell phenotyping and the clinical coursecell phenotyping and the clinical course

The EUROclass classification:The EUROclass classification:

EURO Class classification

>>1%1% B cells (group B+)B cells (group B+)≤1% B cells (group B-)

((smBsmB )+ )+group with group with >2% switched >2% switched memory B cellsmemory B cells

((smBsmB )- )-group with less group with less than or equal to 2% than or equal to 2% switched memory B cellsswitched memory B cells

• The incidence of splenomegaly and granulomatous disease is increased in patients of (smB-) group .The incidence of splenomegaly and granulomatous disease is increased in patients of (smB-) group .

• The incidence of splenomegaly was significantly increased in (smB-CD21 low ) group of patients The incidence of splenomegaly was significantly increased in (smB-CD21 low ) group of patients compared to the subgroups without expanded CD21low B cells (smB- CD21normal, and smB+ compared to the subgroups without expanded CD21low B cells (smB- CD21normal, and smB+ CD21normal). CD21normal).

• Granulomatous disease was also more common in (smB-CD21 low) subgroup, while it was nearly Granulomatous disease was also more common in (smB-CD21 low) subgroup, while it was nearly absent in (smB+CD21normal ) group (Wehr et al.,2008).absent in (smB+CD21normal ) group (Wehr et al.,2008).

1-Monocytes dysfunction:1-Monocytes dysfunction:• Although reduced Igs secretion from B cells is the hallmark of Although reduced Igs secretion from B cells is the hallmark of

CVID, other immunological abnormalities such as monocyte / CVID, other immunological abnormalities such as monocyte / macrophage abnormalities are seen in a considerable proportion macrophage abnormalities are seen in a considerable proportion of patients. of patients.

2-Natural killer cells dysfunction:2-Natural killer cells dysfunction:• A decreased absolute numbers of peripheral blood natural killer A decreased absolute numbers of peripheral blood natural killer

cells have been observed in a subgroup of CVID patients .cells have been observed in a subgroup of CVID patients .

3-Dendritic cells (DCs) dysfunction:3-Dendritic cells (DCs) dysfunction:• Dendritic cells are professional antigen-presenting cells that are Dendritic cells are professional antigen-presenting cells that are

specialized in the uptake of antigens and their transport from specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. DCs from patients with peripheral tissues to the lymphoid organs. DCs from patients with CVID display severely disturbed differentiation and maturation CVID display severely disturbed differentiation and maturation with decreased expression of the co-stimulatory molecules CD80, with decreased expression of the co-stimulatory molecules CD80, CD86 and HLA-DR and impaired IL-12 production (Bayry et CD86 and HLA-DR and impaired IL-12 production (Bayry et al.,2004).al.,2004).

The role of Innate immunity defects in The role of Innate immunity defects in

CVIDCVID

The role of acquired immunity defects in CVIDThe role of acquired immunity defects in CVID

B cells defects in CVID :B cells defects in CVID :

• The production of antibodies by B lymphocyte The production of antibodies by B lymphocyte derived plasma cells is regulated by a derived plasma cells is regulated by a complex array of cellular and molecular complex array of cellular and molecular interactions that take place between antigens interactions that take place between antigens and cells of the innate and adaptive immune and cells of the innate and adaptive immune system .system .

• Late B cell differentiation appears to be defective in Late B cell differentiation appears to be defective in many CVID patients, resulting in normal numbers of many CVID patients, resulting in normal numbers of mature B cells but decreased numbers of functional mature B cells but decreased numbers of functional plasma and/or memory B cells (Ko et al.,2005).plasma and/or memory B cells (Ko et al.,2005).

The stages of B cells development and the defect in CVID and IgAD which occurs The stages of B cells development and the defect in CVID and IgAD which occurs in late stages during activation and differentiation of B cells into plasma cells in late stages during activation and differentiation of B cells into plasma cells ( Kokron et a.,2004).( Kokron et a.,2004).

The role of acquired immunity defects in CVIDThe role of acquired immunity defects in CVID

T cell interaction defects in CVID :T cell interaction defects in CVID :• About one-half of patients with CVID show T cell About one-half of patients with CVID show T cell

dysfunction (Fernández-Ruiz et al., 2007).dysfunction (Fernández-Ruiz et al., 2007).• The abnormalities of T cells in CVID include :The abnormalities of T cells in CVID include :

1.1. The defective thymopoiesis of naive T cells.The defective thymopoiesis of naive T cells.

2.2. The decreased activation and proliferation of T cells. The decreased activation and proliferation of T cells.

3.3. The impairment of T cell dependant humoral immune The impairment of T cell dependant humoral immune response.response.

The role of cytokine defects in CVID :The role of cytokine defects in CVID :• IL-12 synthesis was increased in CVID patients. IL-12 synthesis was increased in CVID patients. • Many Patients with CVID have insufficient production of IL-2 and Many Patients with CVID have insufficient production of IL-2 and

IL-10 Excess.IL-10 Excess.

Known Genetic abnormalities in CVIDKnown Genetic abnormalities in CVID: :

• Four gene mutations are found in about 10% of CVID Four gene mutations are found in about 10% of CVID patients .These four mutated genes are :patients .These four mutated genes are :

1.1. ICOSICOS gene on chromosome 2q. gene on chromosome 2q.

2.2. CD19CD19 gene on chromosome 16p. gene on chromosome 16p.

3.3. TNFRSF13CTNFRSF13C gene on chromosome 22q. gene on chromosome 22q.

4.4. TNFRSF13B on chromosome 17p (Kopecky and TNFRSF13B on chromosome 17p (Kopecky and Lukesova ,2007).Lukesova ,2007).

Clinical Presentation of CVID patientsClinical Presentation of CVID patients

Patients of CVID are at risk for:Patients of CVID are at risk for:

• Chronic lung diseasesChronic lung diseases e.g. e.g. bronchiectasis, and a sarcoid-like lung disease. bronchiectasis, and a sarcoid-like lung disease.

• Gastrointestinal diseasesGastrointestinal diseases e.g. e.g. inflammatory, malignant, and infectious inflammatory, malignant, and infectious complications.complications.

• Liver diseasesLiver diseases:: 10% of patients will have some type of liver disease (HBV, 10% of patients will have some type of liver disease (HBV, HCV, primary biliary cirrhosis) or evidence of granulomatous disease.HCV, primary biliary cirrhosis) or evidence of granulomatous disease.

• Autoimmune diseasesAutoimmune diseases:: the prevalence in CVID is 22% .It includes the prevalence in CVID is 22% .It includes autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura, rheumatoid autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura, rheumatoid arthritis, and pernicious Anemia.arthritis, and pernicious Anemia.

• Granulomatous infiltrationGranulomatous infiltration..

• LymphomasLymphomas

Diagnostic criteria of CVID:Diagnostic criteria of CVID:

• According to the guidelines of the international union of immunodeficiency and the According to the guidelines of the international union of immunodeficiency and the European union of immunodeficiency , common variable immunodeficiency criteria are European union of immunodeficiency , common variable immunodeficiency criteria are classified into :classified into :

probable criteria :probable criteria :

• Male or female patient who has a marked decrease of IgG (at least 2 standard Male or female patient who has a marked decrease of IgG (at least 2 standard deviations below the mean value for age) ,and a marked decrease of at least one of the deviations below the mean value for age) ,and a marked decrease of at least one of the isotypes of IgA ,or IgM, and fulfills all of the following criteria:isotypes of IgA ,or IgM, and fulfills all of the following criteria:

1.1. Onset of immunodeficiency at above 2 years of age.Onset of immunodeficiency at above 2 years of age.2.2. Absent isohemagglutinins and/or poor response to vaccines.Absent isohemagglutinins and/or poor response to vaccines.3.3. Defiened causes of hypogammaglobulinemia have been excluded .Defiened causes of hypogammaglobulinemia have been excluded .

B - possible criteria :B - possible criteria :• Male or female patient who has a marked decrease (at least 2 standard deviations below Male or female patient who has a marked decrease (at least 2 standard deviations below

the mean value for age) in at least one of the major isotypes ( IgG,IgA ,or IgM) and the mean value for age) in at least one of the major isotypes ( IgG,IgA ,or IgM) and fulfills all of the following criteria:fulfills all of the following criteria:

1- Onset of immunodeficiency at above 2 years of age.1- Onset of immunodeficiency at above 2 years of age.2- Absent isohemagglutinins and/or poor response to vaccines.2- Absent isohemagglutinins and/or poor response to vaccines.3- Defiened causes of hypogammaglobulinemia have been excluded (Bernatoweska et 3- Defiened causes of hypogammaglobulinemia have been excluded (Bernatoweska et

al.,2007).al.,2007).

Therapeutic guidelines for CVID:Therapeutic guidelines for CVID:

Prophylaxis by Igs injection :Prophylaxis by Igs injection :

1-1- Intravenous immunoglobulins (IVIG) :Intravenous immunoglobulins (IVIG) :initial dose of 0.5 -0.8 initial dose of 0.5 -0.8 g/kg b. w., next dose approximately 0.4-0.6 g/kg b. w ., every 2-4 g/kg b. w., next dose approximately 0.4-0.6 g/kg b. w ., every 2-4 weeks. The dose depends on the clinical course of the disease ,and weeks. The dose depends on the clinical course of the disease ,and should control infections. IgG levels should achieve at least 5-6 g/ should control infections. IgG levels should achieve at least 5-6 g/ l., and increased in bronchiactasis to 7-9g/l.l., and increased in bronchiactasis to 7-9g/l.

2-2- Subcutaneous IgG :Subcutaneous IgG : The same as above dosage but divided into The same as above dosage but divided into weakly doses of 0.1-0.15g/kg/week.weakly doses of 0.1-0.15g/kg/week.

B-Prophylaxis by antimicrobials :B-Prophylaxis by antimicrobials :

C- Management of infections:C- Management of infections: By increasing IVIG and antibiotics By increasing IVIG and antibiotics according to the pathogen.according to the pathogen.

Summary and conclusionSummary and conclusion

• CVID and PIDs patients had increased rate of infection, CVID and PIDs patients had increased rate of infection, especially respiratory and gastrointestinal infection, especially respiratory and gastrointestinal infection, autoimmune diseases, lymphoid cancer, and autoimmune diseases, lymphoid cancer, and hematological diseases as thrombocytopenia and hematological diseases as thrombocytopenia and hemolytic anemia. hemolytic anemia.

• The The delay in diagnosis and treatmentdelay in diagnosis and treatment of CVID and PIDs of CVID and PIDs leads to leads to increase in morbidity, mortality, and sufferingincrease in morbidity, mortality, and suffering of the patients due to complications . The early discovery of the patients due to complications . The early discovery improves the patient's prognosis and reserved medical improves the patient's prognosis and reserved medical efforts.efforts.

• The absence of official The absence of official registrationregistration in the in the developing countries leads to underestimation of PIDs developing countries leads to underestimation of PIDs incidence, delayed diagnosis, and increased morbidity incidence, delayed diagnosis, and increased morbidity due to complications. Primary hypogammaglobulinemia due to complications. Primary hypogammaglobulinemia accounts for more than 50% of all PIDs, and one of its accounts for more than 50% of all PIDs, and one of its main causes is common variable immunodeficiency main causes is common variable immunodeficiency (CVID).(CVID).

• A good A good health educationhealth education of the medical staff of the medical staff about PIDs and CVID for early diagnosis, official about PIDs and CVID for early diagnosis, official registration , early prophylaxis of infection, and registration , early prophylaxis of infection, and treatment of complications to decrease the morbidity treatment of complications to decrease the morbidity and mortality of PID patients and improve their quality and mortality of PID patients and improve their quality of life.of life.

العالمين رب لله العالمين الحمد رب لله الحمدالحضور السادة و ألساتذتي شكرا الحضور و السادة و ألساتذتي شكرا و

العالمين رب لله العالمين الحمد رب لله الحمدالحضور السادة و ألساتذتي شكرا الحضور و السادة و ألساتذتي شكرا و