A. Classification (Panel 1, Ref [2])

1. Lymphocyte Development Defects [6]
   1. SCID B(+) Cytokine Signalling Deficiency: gamma c, JAK-3, IL7-Ralpha
   2. Defective V(D)J Recombination: Rag-1, Rag-2, Artemis
   3. SCID (-) Impaired DNA Synthesis: Adenosine Deaminase Deficiency
   4. T Cell Deficiency (ZAP-70), CD3zeta chain deficiency
   5. Autosomal recessive agammaglobulinemia (µ Ig alpha bink, lambda 5, CD19)
   6. X-linked agammaglobulinemia (BTK)
   7. Defective Environment (Thymus): DiGeorge Syndrome
2. Antigen Presentation
   1. HLA Class Deficiencies (Bare Lymphocyte Syndrome)
   2. TAP 1/2 Deficiencies
3. DNA Repair Defects
   1. Ataxia Telangiectasia (ATM)
   2. Nijmegen Breakage Syndrome (Nibrin)
   3. DNA Ligase I Deficiency
   4. Bloom Syndrome
   5. SCID B(-): non-homologous end joining defect, Artemis
4. Immunoglobulin (Ig) Class Switch Recombination Defects
   1. HyperIgM Syndrome I: CD40 Ligand (CD40L, CD154) Deficiency
   2. HyperIgM Syndrome II: (AID)
5. Cell Migration Abnormalities
   1. Wiskott-Aldrich Syndrome (WASP)
   2. Leucocyte Adhesion Deficiency (CD18 ß2 integrin)
6. Defective Activation of Intracellular Pathogen Killing Pathway
   1. Susceptibility to mycobacterial infections
   2. Mutations in interferon (IFN) gamma receptor 1 [3], IL12 ß40, or IL12 receptor ß1
7. Defective Killing of Pathogens through Oxidative Burst
   1. Chronic Granulomatous Diseases
   2. Mutations in gp91, p22, p47, p67
8. Cytolytic Pathway Defects
   1. Lymphohistiocytosis (perforin)
   2. Chediak-Higashi Syndrome (lyst)
   3. Griscelli Syndrome (RAB27A)
   4. Familial Hemophagocytic X-linked Proliferative Syndrome (SH2DIA/SAP/DSHP)
9. Abnormal Lymophocyte Apoptosis
   1. IL2 Receptor Alpha Deficiency
   2. Autoimmune Lymphoproliferative Syndrome (ALPS, fas, caspase 10)
10. Overall, at least 71 primary immunodeficiency diseases have been characterized

B. Severe Combined Immunodeficiency (SCID) [15]

1. Profound lack of T lymphocytes (usually with other lineages affected)
2. Several Genetic Lesions Cause SCID [2,6,25]
   1. Common Cytokine Receptor Gamma Chain Mutations, cGamma Chain (~50%) - chromosome (chr) Xq19, involved in IL-2/4/7/9/15 signalling
   2. Adenosine deaminase deficiency (~20%) - T, B, NK defects
   3. Recombinase activating gene 1 or 2 (RAG1, RAG2) null mutants or Artemis mutants (~20%)
   4. Jak-3 Deficiency (6%) - T and NK cell defects
   5. Interleukin-7 receptor alpha chain (1.4%) - T cell and NK cell defects
   6. Cartilage hair hypoplasia (0.7%)
   7. Reticular Dysgenesis (0.7%) - rare autosomal recessive; T, B, NK, myeloid defects
   8. CD3 delta mutations - very uncommon; B cells present, lack of CD3+T and g/d T cells [39]
   9. CD3 epsilon mutations - very uncommon (<0.5%)
   10. CD3 zeta mutations - very uncommon [41]
3. Symptoms
   1. Illness by age 3 months
   2. Present with persistent thrush, diarrhea, cough, morbiliform rash, pneumonias
   3. Failure to thrive
   4. Rapidly fatal viral infections
   5. Maternal lymphocytes delivered transplacentally can cause graft-versus-host disease
4. Diagnosis
   1. Profound lymphopenia (<1000 cells/µL)
   2. Failed thymus development (no thymic shadow seen on chest radiograph)
   3. No antibody response to tetanus toxoid
   4. Serum Ig levels extremely low with rare M component
5. Treatment
   1. ADA Deficiency can be partially treated with ADA injections (PEG-ADA)
   2. Intravenous immunoglobulin (IVIg) or sc Ig may be helpful (~200mg/kg q3-4 weeks) [4]
   3. Bone marrow transplantation (BMT) is the mainstay of therapy [33]
   4. Graft versus host disease develops if patients are given whole blood
   5. The thymic remnant in infants given BMT is sufficient to allow T cell development [22]
   6. Exogenous IL2 has been given to some patients with limited efficacy
6. Gene therapy with insertion of ADA gene into patient's cells is promising
7. Correction of X-Linked SCID [11,37]
   1. Ex vivo gene transfer with defective retroviral vector or gammaretroviral vector
   2. Common gamma chain gene expression >2.5 years after transfected CD34+ cells infused
   3. Thymopoiesis, T and B lymphocytes documented
   4. Peripheral T cell show T cell receptor diversity
   5. B-cells matured and produced increasing rates of somatically mutated immunoglobulin (Ig)
   6. Serum Ig levels restored to level sufficient to avoid IV Ig treatments in some patients
   7. Vaccination stimulated antibody production
8. In utero hematopoietic stem cell transplantation has been used successfully [5]

C. HyperIgM Syndrome [25]

1. Elevated serum IgM with low or absent IgG, IgA, and IgE
2. Two Classes of HyperIgM Syndrome
   1. HyperIgM I: ~80%; patients are male with the X-Linked Form of disease
   2. HyperIgM II: ~20%; most are female; mutations of activation induced deaminase (AID)
3. Etiology of X-linked HyperIgM
   1. Abnormal or absent CD154 (CD40-Ligand, also called gp39) on T cells
   2. B cells are normal but cannot switch from IgM to other isotypes
   3. T cells defects are present but not well understood at this time
   4. T cell defects may be related to dysfunctional dendritic cell - T cell interactions
4. Patients usually present with recurrent bacterial (pyogenic) infections
   1. Streptococcus pneumonia and Haemophilus influenzae are most common
   2. Streptococcus pyogenes and Staphylococcus aureus are less common
   3. Mycoplasma and Ureaplasma infections occur at low serum IgG levels
5. Occurrance of non-bacterial infections, suggest T cell immune deficits
   1. Pneumocystis carinii
   2. Histoplasma capsulatum
   3. Cryptospiridium
   4. Chronic Giardia infections
6. Associated Disease
   1. Neutropenia - corrects with IVIg (or sc Ig)
   2. Autoimmune disorders including hemolytic anemia and thrombocytopenia
   3. Lymphomas and Abdominal Cancers
   4. Biliary tract cancers are associated with chronic cryptosporidial infections
   5. Biliary destruction with cirrhosis also commonly occurs in these patients
7. Treatment
   1. Intravenous Immunoglobulin (IVIg)
   2. IVIg recommended doses is ~250-500mg/kg q4-8 weeks
   3. Maintain serum Ig trough levels of IgG >500mg/dL to reduce infection risk
   4. Allogeneic bone marrow transplantation (BMT)
   5. BMT combined with liver transplantation [21]

D. Agammaglobulinemia

1. About 90% have X linked defect in differentiation of B lymphocytes (Bruton Form)
   1. Reduced production of all Immunoglobulins and B Cells
   2. Developmental block occurs between pre-B and B cells
   3. Mutations in a src-like tyrosine kinase molecule called btk
   4. Murine model is called xid
2. Recessive Form (10%)
   1. ~10% of agammaglobulinemia do not have btk mutations
   2. ~50% of these patients are girls
   3. B cell development is blocked at precursor B cell stage
   4. Mutations in µ heavy chain gene most common cause
   5. Mutations in gamma 5/14-1 surrogate light chain, or in CD79A (Ig-a) have been found [2]
   6. Hypoglobulinemia with CD19 mutations: normal numbers of mature B cells; CD27+ memory B cells and CD5+ B cells reduced [42]
   7. Other mutations have been described as well
3. Affected patients become symptomatic at ~9-12 months of age
   1. This is due to protection by transplacental IgG from mothers
   2. Usually present with recurrent pyogenic infections
   3. Encapsulated organisms are most problematic
4. Common Infections
   1. Otitis media, sinusitis, conjunctivitis
   2. Pneumonia and Pyoderma
   3. H. influenzae and S. pneumoniae are most common organisms
   4. Staph. aureus, S. pyogenes and pseudomonas are less commonly found
   5. Increases in Campylobacter jejuni (bacteremia and cellulitis)
   6. Increased susceptibility to enteroviruses with meningoencephalitis, dermatomyositis
5. Other Problems
   1. Susceptible to poliomyelitis if vaccinated with live virus vaccine
   2. Chronic colonization with Giardia lamblia if infected
   3. ~30% of patients develop large joint arthritis (may be related to Ureaplasma infection)
   4. Severe meningoencephalitis may occur with coxsackievirus or echovirus [7]
6. Treatment
   1. Polyclonal Ig replacement therapy with IVIg
   2. Typical doses are 300mg/kg for adults, 400mg/kg for children, given q4 weeks
   3. Using 2X doses reduces number and duration of infections ~40% [36]
7. Patients rarely live past 3rd or 4th decade
8. Serologic tests (such as HIV, HBV, HCV) are completely unreliable in agammaglobulinemia

E. Wiskott-Aldrich Syndrome [43,44]

1. Classic Triad
   1. Thrombocytopenia: often severe, with abnormally small platelets, bleeding risk
   2. Eczema
   3. Recurrent infections: pyogenic and opportunistic
2. Pathophysiology [44]
   1. X-linked recessive disease due to mutations in chr Xp11.23 gene
   2. The gene on Xp11.23 (called WAS gene) codes for 501 amino acid, proline rich protein
   3. This protein is called Wiskott-Aldrich Syndrome Protein (WASP)
   4. WASP is major regulatory in actin filament assembly and microvesicle formation
   5. Defective signalling in B cells has been documented, particularly to polysaccharide antigens
   6. Abnormal T cell-accessory cell synapse formation reduces antigen presentation efficiency
3. Symptoms and Signs
   1. Usually present during infancy with bloody diarrhea and excessive bruising
   2. Eczema - rash usually age 1-2 years
   3. Recurrent Bloody Diarrhea
   4. Thrombocytopenia - may be marked (platelets are small), associated with bleeding risk
   5. Malignancy - particularly increased risk of lymphoma
   6. Majority of cases are males
   7. Female patients have X-chr inactivation [9] or presence of two mutant alleles [43]
   8. Associated with elevated IgA levels
4. Treatment
   1. Splenectomy for thrombocytopenia
   2. Intravenous immunoglobulin
   3. Vaccinations (non-live vaccines)
   4. Bone Marrow Transplantation

F. MHC Class I Deficiency [20,24]

1. Vasculitis with symptoms very similar to Wegener's Granulomatosis
2. Recurrent upper respiratory infections with purulent sinusitis
   1. Usually present in late childhood with chronic bacterial infections
   2. Progressive degradation of lung tissues can occur with bronchiectasis
3. Vasculitic skin lesions
4. Destruction of nasal and other cartilage
5. No ANCA, anti-MPO or anti-Pr3 antibodies
6. Due to mutations in the TAP (transporter associated with antigen processing) genes
   1. TAP required for Class I MHC expression
   2. Mutations in either TAP1 or TAP2 genes can lead to this syndrome
7. Infections respond to antibiotics
8. Inflammatory lesions may be due to hyperactive NK and gamma-delta T lymphocytes

G. MHC Class II Deficiency [10]

1. Previously called the "Bare Lymphocyte Syndrome"
2. Autosomal Recessive Trait
   1. Mutations do not map to the MHC Class II Locus on chr 6
   2. Four distinct complementation (mutation) groups have been defined
   3. The implicated proteins transcriptionally regulate class II MHC expression
   4. Group A: to chr 15 and is a class II transactivator protein (CIITA)
   5. Groups B,C,D: abnormalities in multimeric regulatory factor protein, RFX
   6. RFX5 is mutated in group C (chr 1q)
   7. Group D: RFXAP (chr 13q)
3. Symptoms
   1. Severe, protracted diarrhea with failure to thrive
   2. Candidiasis, Cryptosporidium infections
   3. Sclerosing cholangitis
   4. Pneumonia
   5. Death by 2nd decade of life
4. Treatment
   1. Bone Marrow Transplantation is only real therapy
   2. In utero hematopoietic transplantation has been used successfully [5]

H. Chronic Granulomatous Disease (CGD) [8,23,28]

1. X linked and autosomal forms, lesions in subunits of Cytochrome b (NADPH oxidase)
   1. Mutations in one or more of 6 genes coding for components of the NADPH oxidase complex
   2. Most common (~70% of CGD) is defect in 65K protein on chr Xp21
   3. This is a mutation in one of the two subunits of cytochrome B (gp91 phox)
   4. Autosomal recessive CGD due to mutaitons in various genes: p47hox (~20% of cases), p22phox (~5%), p67phox (~5%),
   5. Rarely, abnormalities in Rac2, a small GTPase, can cause CGD-like disease
2. Affected Cell Types
   1. NADPH oxidase is present in phagocytes
   2. Neutrophils and macrophages primarily affected. Normal B and T cells
   3. PMNs cannot kill bacteria because of inability to produce superoxide
3. Symptoms
   1. Recurrent pyogenic infections with catalase-positive organisms
   2. Excessive granuloma formation with defective white blood cells
   3. Increased risk of aspirgillosis, including pneumonia [8,35]
   4. Infections wane as patients get older (may be due to protective antibodies)
   5. Recurrent pneumonia, bronchiolitis (relatively uncommon) [40]
   6. Similar to Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
4. Diagnosis
   1. Dihydrorhotamine assay for NADPH oxidase
   2. Results either absent or reduced levels of NADPH oxidase
   3. Levels typically correspond to specific mutations
5. Treatment
   1. TMP-SMX (Bactrim®, Septra®) antibiotic prophylaxis qd
   2. Prolonged courses of additional antibiotics for any infections
   3. Prophylaxis with itraconazole reduces risk of serious and superficialc infections [32]
   4. Aggressive surgical treatment of abscesses
   5. Interferon gamma
   6. Granulocyte transfusions
   7. Allogeneic (HLA-matched sibling) transplantation with T cell graft ablation [31]
6. Interferon gamma (IFNg) [12]
   1. Improves symptoms, reduces infection rate
   2. Recombinant IFNg (Actimmune®) is approved for prophylaxis in CGD
   3. Dose is 50µg/m2 3X/week sc
   4. Well tolerated, reduces infections by ~70%

I. Myeloperoxidase Deficiency [23,28]

1. Most common neutrophil (PMN) defect
2. Due to mutations in myeloperoxidase
   1. Autosomal recessive trait, ~1/1000 persons
   2. Heme enzyme which catalyzes oxidation of Cl-, Br-, I- (or SCN-) by hydrogen peroxide:
   3. Cl- + H2O2 --> OCl- + H2O
   4. OCl- is antimicrobial (but redundant systems are present)
3. Symptoms
   1. Minimal symptoms unless another defect present (such as diabetes mellitus)
   2. May be detected on an automated differential count showing abnormally sized PMNs
   3. Infections most commonly seen are due to Candida (yeast)
   4. Skin infections are also common
4. May present similar to CGD since oxidative burst functions are abnormal

J. Thymus and Parathyroid Aplasia (DiGeorge Syndrome) [14]

1. Failure of 3rd and 4th pharyngeal pouches to develop at 12th week gestation
2. Therefore, both thymus and parathyroid glands fail to develop
3. Failure of aorticopulmonary septum to spiral
4. Thymic Abnormalities
   1. Patients have T cell precursors but these fail to mature normally
   2. Abnormal thymic epithelium is believed to play a role
   3. Patients with profound T cell deficiency are said to have Complete DeGeorge Syndrome
5. Other Symptoms
   1. Hypoparathyroidism: lack of PTH leads to hypocalcemia
   2. Congenital Heart Disesase See Cad "Congenital Heart Disease"
6. Genetics
   1. ~50% of patients are hemizygous for chr 22q11
   2. Deletion of TBX-1 gene on chr 22q11 is believed to be the cause
   3. TBX-1 plays major role in thymius and parathyroid development
   4. Other syndromes are associated with chr22q11 hemizygosity [14]
   5. Most common of these is velocardiofacial syndrome
   6. Rarer patients with DiGeorge are hemizyous for chr 10p13
7. Treatment
   1. Allogeneic (HLA-indentical) Bone Marrow or Allogeneic Stem Cell Transplantation
   2. Allogeneic, cultured, postnatal (day 2-35) thymic tissue transplantation [19]

K. Ataxia Telangiectasia [25]

1. Rare autosomal recessive disorder
   1. Carriers represent ~1.5% of population
   2. Disease frequency <1:10,000
   3. Median lifespan is 20 years for homozygotes
   4. Heterozygous of ATM mutations die 7-8 years earlier than age-matched controls [27]
   5. Heterozygotes die early from cardiovascular and neoplastic causes [27]
2. Defective DNA Repair [26]
   1. Mutation on ATM gene on chr 11q22-23
   2. ATM gene codes for DNA repair protein involved in mitogenic signal transduction
   3. Also involved in meiotic recombination and control of cell cycle
   4. One domain is homologous to radiation repair genes RAD3 and MEC1
   5. Other domain is homologous to a phosphatidylinositol-3-kinase (DNA dependent kinase)
   6. Altered cell signalling and DNA repair appears to be result of abnormal gene product
   7. ATM kinase activity can phosphorylate BRCA1 protein and activate it
3. Symptoms
   1. Ataxia due to cerebellar Purkinje fiber degeneration
   2. Neuromuscular degeneration, progression to wheelchair requirements, usually by age 10
   3. Dilation of capillary vessels, shows up on skin (telangiectasias)
   4. Immune abnormalities
   5. Cancer risks: 85% are lymphomas or leukemias, 15% are other types of cancer
   6. Nearly 100X increased risk of B cell (B-CLL) and prolymphocytic T cell leukemias
   7. Increased risks of other cancers
   8. Hypersensitivity to radiation
4. Immune Abnormalities
   1. Primary defect in T cells
   2. B cell (Ig) defects occur, usually IgA deficiency is first to appear
   3. Defective IgA deficiency is prevalent in 50-80% of the patients
   4. Abnormal expression of ATM gene found in nearly 50% of chronic B cell leukemias [17]
5. Other Findings
   1. Growth retardation and premature aging
   2. Chromosomal instability
   3. Increased alpha-fetoprotein
   4. Increase in lymphomas

L. Chediak-Higashi Syndrome [28]

1. Autosomal recessive
2. Defect in lysosomal trafficking regulator protein
   1. Mutation in gene LYST
   2. This is a cytoplasmic protein involved in forming vacuoles, function, protein transport
   3. Fusion of gian granules with phagosomes is delayed
   4. Affects all lysosome-granule containing cells
3. Manifest primarily as Neutrophil Dysfunction
   1. Problem with degranulation and motility
   2. Thus, PMNs typically have extremely large azurophilic (lysosomal) granules
   3. Mild neutropenia is present
4. Recurrent pyogenic infections
   1. Especially S. aureus and ß-hemolytic streptococcus
   2. Severe periodontal disease
   3. Disease culminates in 85% with fatal infiltration of tissue by CD8+ T cells and macrophages
   4. This syndrome requires lympholytic agents
5. Other Symptoms
   1. Nystagmus and progressive peripheral neuropathy (in patients who live >20 years)
   2. Mild mental retardation
   3. Partial ocular and cutaneous albinism
   4. Platelet dysfunction with easy bruising

M. Hyper-IgE Syndrome (Job's Syndrome) [18]

1. Autosomal dominant inheritance with variable penitrance and spontaneous forms
2. Symptoms and Signs
   1. Common pulmonary, bone, upper airway infections, especially sinusitus
   2. "Cold" cutaneous and lung cyst-forming abscesses
   3. Eczematoid rashes
   4. Common infections: Staphylococcus ssp, H. Influenzae, mucocutaneous candidiasis
   5. Kyphoscoliosis and hyperextensible joints
   6. Increased fractures not clearly associated with osteopenia
   7. Abnormal resorption of primary teeth
   8. Peculiar, coarse facies including enlarged (wide) nose
3. Pathophysiology
   1. Multisystem disease affecting immune, connective, skeletal systems
   2. Very high serum IgE levels
   3. Elevated serum IgE anti-S. aureus (this is an inappropriate Ab response)
   4. Hypereosinophilia often found
   5. Neutrophil defects
   6. May have increased incidence of B cell lymphoma [16]
4. Pathogenesis [45]
   1. Defective IL6 signalling, mainly through STAT3, identified [45]
   2. Mutations in STAT3 transcription factor in sporadic and dominant forms
   3. Affect DNA-binding and SRC homology (SH2) domains of STAT3
   4. Overproduction of pro-inflammatory cytokines seen
   5. Overstimulation of IL4 Responses also postulated [13]
5. Diagnosis
   1. Elevated serum IgE
   2. Mild eosinophilia
   3. Appearance typical of disease
   4. Failure of resorption of primary teeth
6. Treatment
   1. Interferon gamma is not effective [9]
   2. Prolonged antibiotic therapy
   3. IVIg improves severe eczema and decreases IgE production in these patients
   4. IL4 blockade may be effective [13]
   5. Allogeneic stem cell transplantation [16]

N. Complement Deficiency [29,32]

1. Classical Pathway Review
   [Figure] "Complement System"
   1. C1+C2/4 activates C3 converted to C3a (anaphylatoxin) and C3b
   2. C3b acts on C5 converted to C5a (major anaphylatoxin) + C5b
   3. C5b is C6 activator converted to C6a, which activates membrane attack complex
2. Defiency of various components of classical pathway have been described
   1. Deficiency of C1q or C4 (C1r, C1s very rare) has ~75% risk of developing systemic lupus
   2. Deficiency of C2 has ~30% risk of developing systemic lupus
   3. C4 deficiency occurs in up to 4% of the population
3. C3 is especially important in Gram+ and encapsulated organisms
   1. Deficiency in this protein leads to post-infectious immune complex disease
   2. Also have increased infections with following organisms:
   3. Gram Positive: Staphylococcus ssp., S. pneumoniae, Peptostreptococcus ssp
   4. Gram Negative: H. influenza, N. gonorrhea
4. Alternative Pathway
   1. C3 activated by G- wall, properdin, then meshes with classical path
   2. In constant low state of "On", inhibited by Factor I
   3. In vitro, most important for G-. Questionable in vivo
   4. May have role in tumor surveillance
5. Any terminal complement protein (C5-C9) deficiency increases risk of Neisseria infection

O. Common Variable Immunodeficiency (CVID) [7]

1. Heterogeneous collection of syndromes
   1. 10-20% of persons have no identifiable peripheral B cells
   2. Mature B cells in 80-90% of persons fail to differentiate to plasma cells
   3. Prevalence is about 1:100,000; Male = Female
2. Recurrent Infections
   1. Respiratory infections: Sinusitis, Otitis media, Bronchitis and Pneumonia
   2. Encapsulated organisms (S. pneumoniae and H. influenzae) most common
   3. Gastrointestinal Disease: Giardia lamblia and enteric bacterial pathogens
   4. Herpes zoster (shingles): up to 20% of patients
   5. Herpes simplex and Epstein-Barr Virus incidence increased
3. Autoimmune Disease
   1. ~20% of CVID patients develop autoimmune processes
   2. Most common are Coombs' positive hemolytic anemia and autoimmune ITP
   3. Neutropenia ± anti-granulocyte Abs may occur
   4. Pernicious anemia (~10% of CVID)
   5. Splenomegaly in 40-70%
4. Diagnosis
   1. Serum Ig levels much decreased: IgG and IgA consistently decreased (IgM variable)
   2. Recurrent Infections (as above)
5. Intravenous Ig replacement therapy is very effective [36]

P. IgA Deficiency [7]

1. One of most common deficiencies, presents in adult life
2. Often occurs with IgG subclass deficiency
   1. May be congenital or acquired
   2. Likely represents primary defect in Ig class switching
3. Presents with recurrent mucosal infections
4. Treatment is difficult
   1. Chronic antibiotic suppression therapy may be tried
   2. Intravenous Ig is generally contraindicated as IgA is a neoantigen
   3. Therefore, patients with severe IgA deficiency mount an immune response to IgA
   4. Transfusions or other plasma containing products should preferably come from IgA deficient donors or increased risk of
   5. Subsequent treatments can cause anaphylactic responses

Q. Signalling Defects

1. Interleukin 2 Receptor (IL-2) Alpha Chain (CD25) Deficiency [25]
   1. Mutations on CD25 gene on chromsome 10p14-15
   2. Reported in only a single infant
   3. Overproduction of T cells
   4. Serum levels of IgG and IgM elevated; IgA levels low
   5. Defective repsonse to CD3, phytohemagglutinin and IL2
2. Interferon Gamma Defects
   1. Mutations in IFNg-receptor binding or IFNg-receptor signalling chains
   2. Same phenotype as IL-12 signalling deficiencies
   3. Infections with intracellular microorganisms most common
   4. Severe mycobacterial disease
   5. Failure to form granulomas
   6. Late onset osteomyelitis may be seen
3. Interleukin 12 Defects
   1. Due to mutations in IL-12 receptor ß1 chain or in IL-12 p40 chain
   2. Same phenotype as IFNg signalling defect
4. Fc-Gamma Receptor Polymorphism
   1. Fc-Gamma used for binding IgG complexed with bacteria
   2. Polymorphism associated with reduced opsonization and signalling
   3. Homogygous polymorphism associated with increased risk for bacterial pneumonia [29]

R. Leukocyte Adhesion Deficiency [28]

1. Two types of adhesion abnormalities described (Types I and II)
2. Both are primarily phagocyte deficiency diseases
3. Type I
   1. Absent or reduced CD18 expression
   2. Severe periodontitis usually with early tooth decay
   3. Recurrent infections of oral and genital mucosa
   4. Skin, intestinal and respiratory tract infections
4. Type II
   1. Defect in carbohydrate fucosylation (unknown mutation)
   2. Associated with growth retardation, dysmorphic features, neurologic deficiets
   3. No fucosylation of ligants for P- and E-selectins
   4. Treatment with oral fucose is helpful

S. Mannose Binding Lectin (MBL) Insufficiency [29,30,32]

1. MBL is a serum protein involved in innate immunity
2. MBL2 gene on chrom 10 codes for MBL in humans
3. MBL binds to high mannose and N-acetylglucosamine sugars on microorganisms
4. This leads to complement activation by MBL-associated serine proteases
5. In addition, MBL binds to receptors on phagocytes
6. Several variant alleles which all lead to lower MBL levels have been identified
7. Heterozygosity of MBL associated with 5-10X reduced MBL levels and 2X increased risk of acute respiratory infections in children <2 years [30]

T. X-Linked Proliferative Syndrome

1. Also called Purtilo's Syndrome
2. Due to mutations in the SAP/SH2DIA/DSHP gene
   1. Codes for SLAM associated protein
   2. SLAM is signalling lymphocyte activation molecule
   3. SAP also associates with 2B4 signalling molecule on NK cells
   4. Defects in SAP lead to overproduction of defective cytolytic and some helper T cells
   5. These abnormal T cells infiltrate organs and cause progressive damage
3. Disease manifestations include:
   1. Uncontrolled polyclonal CD8+ T cell activation leading to severe organ damage
   2. This syndrome is often referred to familial hemophagocytic proliferative syndrome
   3. It includes loss of B cells and progressive hypoglobulinemia
   4. Chronic Epstein-Barr Virus infections develop and may progress
   5. The other variant is frank early lymphomas
4. No patients older than 40 years have been described

U. IPEX Syndrome [34]

1. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome
2. Due to mutations in FOXP3 gene
   1. Normally expressed primarily in CD4+ T lymphocytes
   2. CD4+ T cell hyperproliferation is central to this disease
3. Symptoms Appear in Infancy
   1. Diarrhea
   2. Ichthyosiform dermatitis
   3. Insulin dependent diabetes mellitus
   4. Thyroiditis
   5. Hemolytic anemia
4. Treatment
   1. Parenteral nutrition
   2. Immunosuppressive agents show some palliation
   3. Allogeneic transplantation provided some palliation in one patient [34]
5. Disease is typically fatal within 5 years

V. Interferon Gamma (IFNg) Receptor 1 Deficiency [3]

1. Autosomal dominant and recessive forms
2. Sever infections with mycobacteria
3. Recessive patients have earlier onset (age 3) versus dominant (age 13)
4. Recessive had more disseminated mycobacterial disease than dominant form
5. Mycobacterium avium complex (MAC) osteomyelitis more common in dominant than recessive

W. Rag Mutations with Hypofunction

1. Omenn Syndrome
   1. Missense mutations of RAG1 or RAG2 allowing residual Rag activity
   2. Hepatosplenomegaly, lymphadenopathy
   3. Eosinophilia, elevated serum IgE levels, oligoclonal T cell populations
   4. T cells infiltrate mainly skin and gastrointestinal tract
2. Rag Mutations and Granulomas [46]
   1. Diminished Rag activity due to function-suppressing but still active Rag mutations
   2. Limited maturation of T and B cells and hypogammaglobulinemia
   3. Sparse thymic tissue
   4. Extensive granulomatous disease of skin, mucous membranes, internal organs

References

1. Puck JM. 1998. JAMA. 278(22):1835
2. Fischer A. 2001. Lancet. 357(9271):1863
3. Dorman SE, Picard C, Lammas D, et al. 2004. Lancet. 364(9451):2113
4. Subcutaneous Immune Globulin. 2007. Med Let. 49(1258):31
5. Flake AW and Zanjani ED. 1997. JAMA. 278(11):932
6. Rudd CE. 2006. NEJM. 354(18):1874
7. Sicherer SH and Winkelstein JA. 1998. JAMA. 279(1):68
8. Harris JB, Michelow IC, Westra SJ, Kradin RL. 2008. NEJM. 359(2):178 (Case Record)
9. Parolini O, Ressmann G, Haas OA, et al. 1998. NEJM. 338(5):291
10. Villard J, Lisowska-Grospierre B, van den Elsen P, et al. 1997. NEJM. 337(11):748
11. Gaspar HB, Parsley KL, Howe S, et al. 2004. Lancet. 364(9452):2181
12. Gallin JI, Farber JM, Holland SM, Nutman M. 1995. Ann Intern Med. 123(3):216
13. Hershey GKK, Friedrich MF, Esswein LA, et al. 1997. NEJM. 337(24):17,20
14. Kobrynski LJ and Sullivan KE. 2007. Lancet. 370(9596):1443
15. Rosen FS and Bhan AK. 1998. NEJM. 338(24):1752 (Case Record)
16. Nester TA, Wagnon AH, Reilly WF, et al. 1998. Am J Med. 105(2):
17. Stankovik T, Weber P, Stewert G, et al. 1999. Lancet. 352(9146):26
18. Grimbacher B, Holland SM, Gallin JI, et al. 1999. NEJM. 340(9):692
19. Markert ML, Boeck A, Hale LP, et al. 1999. NEJM. 341(16):1180
20. Moins-Teisserenc H, Gadola SD, Cella M, et al. 1999. Lancet. 354(9190):1598
21. Hadzic N, Pagliuca A, Rela M, et al. 2000. NEJM. 342(5):320
22. Patel DD, Gooding ME, Parrott RE, et al. 2000. NEJM. 342(18):1325
23. Babior BM. 2000. Am J Med. 109(1):33
24. Klein J and Sato A. 2000. NEJM. 343(11):782
25. Buckley RH. 2000. NEJM. 343(18):1313
26. Haber D. 2000. NEJM. 343(21):1566
27. Su Y and Swift M. 2000. Ann Intern Med. 133(10):770
28. Lekstrom-Himes JA and Gallin JI. 2000. NEJM.343(23):1703
29. Winkelstein JA and Childs B. 2001. JAMA. 285(10):1348
30. Koch A, Melbye M, Sorensen P, et al. 2001. JAMA. 285(10):1316
31. Horwitz ME, Barrett AJ, Brown MR, et al. 2001. NEJM. 344(12):881
32. Walport MJ. 2001. NEJM. 344(14):1058
33. Flake AW, Roncarolo MG, Puck JM, et al. 1996. NEJM. 335(24):1806
34. Baud O, Goulet O, Canioni D, et al. 2001. NEJM. 344(23):1758
35. Cathebras P, Sauron C, Morel F, Stasia MJ. 2001. Lancet. 358(9278):294 (Case Report)
36. Eijkhout HW, van der Meer JWM, Kallenberg CGM, et al. 2001. Ann Intern Med. 135(3):165
37. Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. 2002. NEJM. 346(16):1185
38. Gallin JI, Alling DW, Malech HL, et al. 2003. NEJM. 348(24):2416
39. Dadi HK, Simon AJ, Roifman CM. 2003. NEJM. 349(19):1821
40. Lukela M, DeGuzman D, Weinberger S, Saint S. 2005. NEJM. 352(1):64
41. Rieux-Laucat F, Hivroz C, Lim A, et al. 2006. NEJM. 354(18):1913
42. Van Zelm MC, Reisli I, van der Burg M, et al. 2006. NEJM. 354(18):1901
43. Puck JM and Candotti F. 2006. NEJM. 355(17):1759
44. Binder V, Albert MH, Kabus M, et al. 2006. NEJM. 355(17):1790
45. Holland SM, DeLeo FR, Elloumi HZ, et al. 2007. NEJM. 357(16):1608
46. Schuetz C, Huck K, Gudowius S, et al. 2008. NEJM. 358(19):2030