Primary Immune Deficiencies (PIDs): Diseases Caused by Defective Immunity

Question 1

How are primary immune deficiencies?

Answer 1

• PID can be caused by a mutation in various regions of the gene linked to the disease. Some mutations may cause a severe form of PID whereas others just mild one. For example, there are PIDs in which mutations happening in enzymes may result in either “no enzymatic activity at all” or a range of the outcomes with a “partial decrease in enzymatic activity”.
• For educational purposes, immunology textbooks have a tendency to consider/describe any PID as a condition in which activity or expression of the mutated gene is completely abolished causing a severe form of PIDs. However, mild forms of PIDs characterized by partial loss of function of the mutated genes represent the majority of cases in clinical practice.
• For example, “leaky” deficiencies in RAG1/RAG2 enzymes allow for partial function of these recombination enzymes resulting in an atypical form of Severe Combined Immune Deficiency known as OMENN SYNDROME (see below).
• Such discrepancies between information in textbooks and clinical practice of PIDs may produce some level of confusion. To resolve it, let’s agree on the following:
• When you will take SFM exam and step I Board Examination, think of severe forms of PIDs only …
• When you take Step 2 Clinical Knowledge Examination, remember that PIDs can be manifested by a partial loss of function leading to atypical PIDs.

Question 2

What are Warning Signs of Immunodeficiency Disorder?

Answer 2

PAST MEDICAL HISTORY

• Eight or more ear infections in one year.
• Two or more serious sinus infections in one year.
• Two or more bouts of pneumonia in one year.
• Two or more deep-seated infections, or infections in unusual areas.
• Recurrent deep skin or organ abscesses.
• Need for iv antibiotic therapy to clear infection.
• Infections with unusual or opportunistic organisms.
• Family history of primary immunodeficiency.

Question 3

What is Adenosine Deaminase?

Answer 3

ADENOSINE DEAMINASE converts toxic for lymphocytes deoxyadenosine into deoxyinosine, which is not harmful.

Question 4

What is Artemis?

Answer 4

ARTEMIS is an enzyme in VDJ recombination that serves to repair double strand breaks.

Question 5

How do we test for PID?

Answer 5

Differential count of blood cells: screens for T-cell, B-cell, T/B cell defects. look for Decreased numbers of T cells, B cells, or platelets

DTH skin test: screens for T cell defects. if Negative – possible impaired T-cell response

Serum IgG, IgM, and IgA: screens for Humoral immunodeficiency, look for Decrease in any or all Igs

Ab testing to specific Ag after immunization: screens for Humoral immunodeficiency, look for Decrease of absent Ab response to vaccination

Total hemolytic complement assay: screens for Complement deficiency, look for Decrease or absent components in classical pathway

Nitroblue tetrazolium test: screens for Phagocytic disorder, look for Abnormal test result

Question 6

What is Severe Combined Immune Deficiencies (SCIDs)?

Answer 6

Are associated with profound DEFICIENCIES of T-cell and B-cell functions and sometimes NK cell function.

• Are typically associated with SEVERE LYMPHOPENIA.
• Are characterized by SEVERE OPPORTUNISTIC INFECTIONS, chronic diarrhea, and failure to thrive.
• A fetus with SCID is at RISK of abortion due to INABILITY to reject the maternal T cells that may cross the placenta into the fetal circulation.

AVOID ALL LIVE VIRAL VACCINES

Question 7

What happens in Adenosine Deaminase (ADA) Deficiency?

Answer 7

IMMUNOPHENOTYPE T -, B -, NK -

Absent or low IgG, IgA, and IgM

AVOID ALL LIVE VIRAL VACCINES

• ADA deficiency was the first immunodeficiency in which the specific molecular defect was identified.
• ADA deficiency is an AUTOSOMAL RECESSIVE disorder.
• ADA deficiency is the second most common CAUSE of SCID (15%).
• ADA is essential for the METABOLIC FUNCTION of various cells, especially T- cells.
• ADA deficiency leads to an ACCUMULATION of toxic for lymphocytes metabolic by-products deoxyadenosine.
• Hematopoietic stem cell transplantation (HSCT) is the definitive TREATMENT for ADA deficiency patients.

Question 8

What happens in (PNP) Deficiency Purine Nucleoside Phosphorylase Deficiency?

Answer 8

IMMUNOPHENOTYPE T -, B +, NK +/-

Normal IgG, IgA, and IgM

AVOID ALL LIVE VIRAL VACCINES

• PNP deficiency is a rare AUTOSOMAL RECESSIVE form of SCID that accounts for 4% of all SCID cases.
• PNP deficiency leads to an ACCUMULATION of intracellular deoxyguanosine triphosphate (dGTP). This metabolite is toxic to lymphocytes, leading to a DECREASE in peripheral T cell numbers, but B cell numbers are NORMAL.
• The ONSET can occur during infancy (with a classic SCID phenotype) or later in life, a milder form.
• AUTOIMMUNE DISORDERS are also common and include hemolytic anemia, thyroid disease, arthritis, lupus.
• HSCT is the definitive TREATMENT for PNP deficiency patients.

Question 9

What happens in Artemis Deficiency?

Answer 9

IMMUNOPHENOTYPE T -, B -, NK +

Absent or low IgG, IgA, and IgM

AVOID ALL LIVE VIRAL VACCINES

• Mutations in the gene for Artemis cause a rare form of AUTOSOMAL RECESSIVE RADIOSENSITIVE SCID.
• PRESENTATION occurs in infancy with diarrhea, candidiasis, and infections with opportunistic bacteria Pneumocystis jiroveci.
• T and B CELLS are absent but NK CELL NUMBERS are normal.
• Patients have an increased risk of developing LYMPHOMAS.
• The diagnosis of Artemis deficiency is suggested by a T-B-NK+ SCID phenotype and RADIOSENSITIVITY.
• HSCT is the definitive TREATMENT for patients with Artemis Deficiency.

Question 10

What happens in RAG1/RAG2 Deficiency?

Answer 10

IMMUNOPHENOTYPE T -, B -, NK +

Absent or low IgG, IgA, and IgM

• RAG1 or RAG2 deficiency is a rare form of AUTOSOMAL RECESSIVE disorder causing SCID.
• Defects in RAG1 or RAG2 cause IMPAIRED V(D)J RECOMBINATION and this leads to defective expression of the pre-TCR and pre-BCR.
• PRESENTATION occurs in infancy with diarrhea, candidiasis, and infections with opportunistic bacterium Pneumocystis jiroveci.
• LEAKY RAG1/RAG2 defects allow for partial function of RAG1/RAG2 can give rise to atypical form of SCID known as OMENN SYNDROME.
• Omenn syndrome is characterized by severe erythroderma, splenomegaly, eosinophilia, and high IgE.
• HSCT is the definitive TREATMENT for RAG1/RAG2 deficiency patients.

Question 11

What happens in Deficiency of Jak3?

Answer 11

IMMUNOPHENOTYPE T -, B +, NK -

Very low IgG, IgA, and IgM

AVOID ALL LIVE VIRAL VACCINES

• A SCID caused by a MUTATION in a gene that encodes a lymphocyte Janus kinase 3 (Jak3).
• Jak3 deficiency accounts for approximately 7% of all SCID.
• Inherited as an AUTOSOMAL RECESSIVE trait.
• Both BOYS and GIRLS can be equally affected.
• Causes DEFECT in IL-2 receptor signaling.
• HSCT is the definitive treatment for Jak3 deficiency patients.

Question 12

What is DiGeorge Syndrome (DGS)?

Answer 12

IMMUNOPHENOTYPE T -, B +, NK +

Normal IgG, IgA, and IgM

• A COMPLETE DGS is classic example of T-cell deficiency.
• Most cases result from a MICRODELETION of 22q11.2 region containing more than 35 genes .
• THE CLASSIC TRIAD for DGS includes cardiac anomalies, hypocalcemia, and hypoplastic thymus leading to T-cell immune dysfunction.
• LOW T-CELL NUMBERS are present in 80% of patients with 22q11.2 deletion syndrome.
• HUMORAL IMMUNITY is intact in most patients.
• DGS patients commonly suffer from frequent upper respiratory infections.
• LIVE VIRAL VACCINES are generally given to patients who have a CD8 T-cell count > 300 cells/mm3.

Question 13

What are Selective B Lymphocyte Immunodeficiencies?

Answer 13

• ANTIBODY DEFICIENCIES are the most common immune deficiencies accounting for nearly half of all conditions.
• Antibody deficiencies range from generalized agammaglobulinemia to selective immunoglobulin (Ig) (sub)class deficiencies.

Question 14

What is AGAMMAGLOBULINEMIA?

Answer 14

Primary agammaglobulinemia is most commonly inherited as an X-linked trait linked to mutation in Bruton tyrosine kinase (BTK) but autosomal recessive (AR) forms also exist.

Early B-CELL DEVELOPMENT is arrested at the pre-B-cell stage  circulating B cells are usually absent or present in very low numbers.

Question 15

What happens in X-linked Btk Deficiency?

Answer 15

IMMUNOPHENOTYPE B –, T + , NK +

No IgG, IgM, IgA

• This disorder was clinically described by Dr. Bruton in 1952.
• A mutation in tyrosine kinase was uncovered in 1993. It was named Bruton tyrosine kinase (BTK).
• It is X-LINKED disorder with a frequency of approximately 1:250,000 males.
• Caused by DEFECT in rearrangement of the Ig heavy chain genes.
• DIAGNOSIS: in 5-6-month old infants.
• Titers of all serum antibodies IgG, IgA, IgM are totally absent or very low.
• HSCT is the definitive treatment for patients with Btk kinase deficiency.

Question 16

What are Isolated IgG Subclass Deficiencies?

Answer 16

IMMUNOPHENOTYPE B + , T + , NK +

Some IgG subclasses LOW; normal IgM, IgA, IgE

• Characterized by decreased CONCENTRATIONS of one or more IgG subclass(es).
• Caused by DEFECTS in several genes.
• Isolated IgG subclass deficiency is usually asymptomatic but may be associated with RECURRENT VIRAL/BACTERIAL INFECTIONS, frequently involving the respiratory tract.
• Low levels of IgG2 are frequently associated with poor responses to polysaccharide Ags in children.
• The IgG4 levels vary widely and many healthy people have no IgG4.

Question 17

What is IgA Deficiency?

Answer 17

THE INCIDENCE is relatively high – approximately 1 in 700 individuals. Most affected individuals ARE HEALTHY. Multiple genes are involved.

PATHOGENIC MECHANISM – IgA secreting B cells may have disorders of maturation or terminal differentiation.

IMMUNOPHENOTYPE B + , T + , NK +

No IgA; normal IgG & IgM

• THE PREVALENCE may be higher in male patients.
• DIAGNOSIS – more than 85% present with recurrent infections, typically with encapsulated bacteria.
• About 50% of IgA-deficient PATIENTS are asymptomatic due to the translocation of IgM across the mucosal epithelium.
• ANTIBODIES - IgA titers are undetectable or very low, IgG and IgM are normal.
• Patients with IgA deficiency often develop AUTOIMMUNE DISEASES and ALLERGY.
• Patients with undetectable IgA levels may have serum anti-IgA IgG which has been linked to the development of non-IgE mediated ANAPHYLAXIS in response to an intravenous immunoglobulin (IVIG) transfusion.

Question 18

What are Hyper IgM Syndromes (HIGM)?

Answer 18

IMMUNOPHENOTYPE B + , T + , NK +

High IgM; low IgG & IgA

A GROUP OF DISEASES characterized by impaired Ig class switching and somatic hypermutation.

HIGM patients have NORMAL numbers of peripheral B cells, but LOW numbers of CD27-positive memory B cells

Question 19

What is Hyper IgM Syndrome?

Answer 19

IMMUNOPHENOTYPE B + , T + , NK +

High IgM; low IgG & IgA

• Patients with HIGM syndromes have an increased SUSCEPTIBILITY TO BACTERIAL INFECTION.
• Example – the X-LINKED HIGM due to mutations in the CD40L gene: – CD40L binds CD40 expressed on B cells triggers terminal differentiation of B cells associated with: » CLASS SWITCHING » SOMATIC HYPERMUTATION
• X-LINKED CD40L DEFICIENCY (male only) is responsible for 2/3 of all cases.
• AUTOSOMAL CD40 DEFICIENCY (female and male) deficiency accounts for 1/3 of all cases.
• HSCT is the definitive treatment for patients with Hyper IgM Syndrome.

Question 20

What is TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY?

Answer 20

IMMUNOPHENOTYPE B + , T + , NK +

Low IgG/IgA ; IgM normal or low

• MATERNAL IgG in the infant disappear after birth in 6 months with a half-life of 25-30 days.
• INTRINSIC IgG production usually begins immediately after birth.
• In TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY, intrinsic Ig production is delayed for up to 36 months.
• Result —> LOW IgG and IgA concentrations, but IgM concentration may be NORMAL or LOW.
• Delayed Ig production results in INCREASED SUSCEPTIBILITY to sinopulmonary infections.
• In the majority of patients Ig concentrations normalize between 2 and 4 years of age.

Question 21

What is Common Variable Immune Deficiency (CVID)

Answer 21

• A heterogeneous GROUP OF DISEASES associated with HYPOGAMMAGLOBULINEMIA.
• GENETICS – mutations in receptors for B cell growth factors (maturation/activation) and costimulators (T-B collaboration).
• THE INCIDENCE – is estimated at 1 in 25,000 individuals.
• AUTOSOMAL DISORDER - both males and females are equally affected.

Most cases of CVID remain genetically remain uncharacterized

IMMUNOPHENOTYPE B –/+ , T + , NK +

LOW IgG and IgA; sometimes low IgM

CVID is characterized by a DEFECT in Ab production associated with HYPOGAMMAGLOBULINEMIA.

• The NUMBER of circulating B cells is reduced or normal.
• B cells fail to differentiate into plasma cells which secrete Abs.
• It is diagnosed based on a HISTORY of recurrent pyogenic sinopulmonary infections.
• Patients have RECURRENT INFECTIONS, AUTOIMMUNE DISEASE, and LYMPHOMAS.
• THE ONSET is frequently after 4-5 years of age; however, CVID is usually DIAGNOSED at 20-30 years of age.
• HSCT is the definitive treatment for patients with CVID.

Question 22

Describe a Humoral Immunity Screen

Answer 22

1. measure QUANTITATIVE IMMUNOGLOBULIN LEVELS
   - if normal, check. Diphtheria & tetanus Ab titers induced by previous vaccination
   - if abnormal, Screen cellular immunity
2. If Diphtheria & tetanus Ab titers induced by previous vaccination is abnormal, screen cellular immunity
3. If Diphtheria & tetanus Ab titers induced by previous vaccination is normal, Consider complement, phagocytic defect, other conditions
4. If screen for cellular immunity is abnormal, Consider diagnosis of Common variable immunodeficiency (CVID)
5. If screen for cellular immunity is normal, Consider diagnosis of: 1. X-linked agammaglobulinemia 2. Isolated IgA or IgG 3. Hyper IgM
6. Use this screen for Recurrent sinopulmonary bacterial infections??

Question 23

What happens in Common γ Chain Deficiency (γc or IL-2Rγ)?

Answer 23

IMMUNOPHENOTYPE T -, B +, NK -

Very low IgG, IgA and IgE

AVOID ALL LIVE VIRAL VACCINES

• The MOST COMMON form of SCID (about 45% of all cases).
• This deficiency is inherited as an X-LINKED RECESSIVE trait.
• Gene encodes GAMMA-CHAIN shared by the T-cell growth factor receptor (IL-2Rγ) and other growth factor receptors.
• IL-2Rγ is shared with other cytokine receptors including IL-4, IL-7, IL-9, IL- 15, and IL-21.
• There are no functional B cells since T-cells unable to “help” that results in low IgG, IgA and IgM.
• PATIENTS CLASSICALLY PRESENT in infancy with failure to thrive, severe thrush, opportunistic infections, and chronic diarrhea.
• HSCT is the definitive treatment for patients with γc chain deficiency.

Question 24

What is IL-7Rα Chain Deficiency?

Answer 24

IMMUNOPHENOTYPE T -, B +, NK +

Very low IgG, IgA, IgE

AVOID ALL LIVE VIRAL VACCINES

• IL-7Rα deficiency is an AUTOSOMAL RECESSIVE genetic disorder.
• IL-7 plays a KEY ROLE in early T cell development.
• Lymphocyte subset analysis shows T-B+NK+ PHENOTYPE.
• The IgG, IgA and IgE are low to absent despite the presence of B cells due to absence of T cell co-stimulatory signaling.
• PATIENTS PRESENT with classic SCID infections beginning the childhood– candidiasis, chronic diarrhea, Pneumocystis jiroveci pneumonia, severe viral infections.
• Sequencing of the IL-7Rα gene can confirm the diagnosis.
• HSCT is the definitive treatment for patients with IL-7Rα chain deficiency.

Question 25

What is Bare Lymphocyte Syndrome Type 2 (BLS II)?

Answer 25

IMMUNOPHENOTYPE T + , B +, NK -

Variable hypogammaglobulinemia

A rare AUTOSOMAL RECESSIVE GENETIC disorder causing an HLA class II-negative SCID.

• There is no MHC class II expression on professional APCs that causes a DEFICIENCY in CD4+ T cells.
• Genes for MHC class II on chromosome 6 are intact.
• MUTATIONS are in genes which encode for transcription factors that normally regulate the expression of the MHC II genes.
• Variable HYPOGAMMAGLOBULINAEMIA (mainly IgA and IgG2).
• Leads to RECURRENT respiratory, gastrointestinal, and urinary tracts infections and frequently to death in early childhood.
• HSCT is the definitive treatment for patients with BLS II.

Question 26

What happens in MCH Class I Deficiency?

Answer 26

IMMUNOPHENOTYPE T+ , B+ , NK+

• Caused by a mutation in TAP1 molecules to transfer peptides to ER.
• CD8+ cells and NK cells are functionally deficient that causes recurring viral infections.
• CD4+ cells are normal.
• Normal Ab production .
• Normal DTH (delayed type hypersensitivity).
• HSCT is not recommended.

Peptides generated are carried out into endoplasmic reticulum by transporter proteins (TAP1 and TAP2)

Question 27

What happens in CD3 Complex Deficiencies?

Answer 27

IMMUNOPHENOTYPE T -, B +, NK +

Low IgG, IgA, and IgM

• Deficiencies of the CD3 SUBUNITS (delta, gamma, epsilon, or zeta) can cause an AUTOSOMAL RECESSIVE form of SCID .
• Typically PRESENTS IN INFANCY with lymphopenia and decreased T cell numbers. B cell and NK cell numbers are normal.
• Specific ANTIBODY RESPONSES are typically decreased.
• Patients CLASSICALLY PRESENT in infancy with failure to thrive, opportunistic infections, and chronic diarrhea.
• HSCT is indicated for patients for patients with CD3 Complex Deficiencies.

Question 28

Describe Defects in T-Cell Function

Answer 28

1. Functional defects are observed after T cell maturation is complete. In patients with IPEX (IMMUNODYSREGULATION, POLYENDOCRINOPATHY AND ENTEROPATHY, X- linked syndrome), SELF-REACTIVE T EFFECTOR CELLS ARE NOT INHIBITED, because of a mutation in the FOXP3 results in loss of inhibition by CD4+CD25+ Treg cell.
2. In patients with AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS), defects in either Fas, FasL, caspase-8 or caspase-10 genes results in abrogated formation of the death-inducing signaling complex (DISC) and resistance of effector T cells to apoptosis.

Question 29

Wiskott-Aldrich Syndrome (WAS)

Answer 29

IMMUNOPHENOTYPE T -, B +, NK -

Low IgM; normal Ig, elevated IgA and IgE

WAS is an X-LINKED DISORDER characterized by thrombocytopenia, eczema, cellular and humoral immunodeficiency, autoimmune disease, and malignancy.

• WAS is caused by MUTATIONS in the Wiskott-Aldrich Syndrome Protein (WASP).
• WAS patients develop a COMBINED IMMUNODEFICIENCY: – Decreased IgM, normal IgG, and elevated IgA and IgE levels – T cell lymphopenia – Decreased NK cell cytotoxicity
• Patients have RECURRENT BACTERIAL INFECTIONS with encapsulated bacteria., viral infections and opportunistic infections with Pneumocystis jiroveci and Candida can also occur.

Question 30

What happens when there is a Defect in the IFN-γ–IL-12 AXIS?

Answer 30

POSITIVE REGULATORY LOOP

• Produced by Mφ and DCs IL-12 binds to IL-12R stimulates IFN-γ release by T cells and NK cells.
• Binding of IFN-γ by Mφ cross-link the IFN-γ receptor and activates the production of H2O2 and TNF-α and IL-12 (dimer of subunits p35 and p40). Mutations resulting in increased SUSCEPTIBILITY to nontuberculous mycobacteria have been identified in the genes encoding: – the IFN-γ receptor – the IL-12 receptor – the p40 subunit of IL-12.

Question 31

What happens when there are Defects in IL-12/IFN-γ Pathway?

Answer 31

• IL-12 signaling is ESSENTIAL FOR THE DIFFERENTIATION of naïve T cells into Th1 cells.
• MUTATIONS in the IL-12 or IL-12R genes result in a clinically limited primary immunodeficiency.
• Patients with IL-12 or IL-12R deficiency do not produce Th1 cytokine IFN-γ which is necessary for the control of intracellular bacterial infections.
• Patients typically present with a SELECTIVE SUSCEPTIBILITY to intracellular pathogens such as atypical mycobacteria, candida, and salmonella.
• Patients with IL-12 or IL-12R deficiency also have defects in Th17 cells that accounts for the recurrent fungal infections

Question 32

What happens in Th17 Deficiency?

Answer 32

Activation of INNATE IMMUNE RESPONSES by Candida through PRRs directs the subsequent development of naïve T cells into Th17 cells.

• Th17 deficiency UNUSUAL SUSCEPTIBILITY to chronic mucocutaneous candidiasis.
• The impairment of Th17 cell development is associated with MUTATIONS in genes encoding for either IL-17, IL-17R, or transcriptional factors STAT1, STAT3 or AIRE.
• Prior to the identification of the Th17 deficiency, many patients were categorized as having autosomal recessive HYPER IgE SYNDROME with: – Severe atopic disease (atopic dermatitis, food allergies, asthma) – Recurrent Staph aureus skin abscesses

Question 33

What happens in NK Cell Deficiency (NKD)?

Answer 33

• There are more than 40 IMMUNODEFICIENCIES known to impair NK cells.
• To be considered an NKD, NK cells should represent the major immunologic abnormality in the patient.
• NKD is caused by MUTATIONS in multiple genes.
• NKDs can be divided into 2 major types: – Classical NKD (CNKD) is defined as an absence of NK cells » Example: GATA2 deficiency with NK cell lymphopenia – Functional NKD (FNKD) is defined as the presence of NK cells exhibiting defective NK cell activity without NK cell lymphopenia » Example: Perforin deficiency
• NKDs PRESENT with multiple severe or disseminated viral infections including herpesvirus infections, including varicella pneumonia, disseminated cytomegalovirus (CMV), and herpes simplex virus (HSV).

Question 34

Describe a Cellular Immunity Screen

Answer 34

1. Run CBC/differential + chest X-ray – if no thymus – consider DiGeorge syndrome; SCID (especially Absolute Lymphocyte Count)
2. Run T cell panel. If abnormal, perform Functional testing (mitogen stimulation and Ag stimulation) OR B cell/NK cell CD marker studies
   - if Functional testing (mitogen stimulation and Ag stimulation) is abnormal, consider SCID. Carry out molecular genetic testing or testing for specific enzyme defect
   - if B cell/NK cell CD marker studies are abnormal, SCID – do DNA testing or specific enzyme defect Complete DiGeorge syndrome. Also test for HIV.

Question 35

What is Chronic Granulomatous Disease (CGD)?

Answer 35

Granulomas are masses of immune cells that form at sites of infection or inflammation.

CGD is a PHAGOCYTIC DISORDER characterized by the tendency to form granulomas.

• CGD is the MOST FREQUENT phagocytic primary immunodeficiency.
• MORE COMMON in males than in females.
• Biochemical cause of CGD is an ENZYMATIC DEFICIENCY of NADPH oxidase in phagocytes.
• CGD phagocytes FAIL to generate superoxide anion and other O2 radicals.
• Results in DEFECTIVE ELIMINATION of extracellular pathogens such as bacteria and fungi.
• Patients with CGD susceptible to RECURRENT INFECTION with catalase- positive organisms (e.g., staphylococci).

Question 36

What happens in G6PD Deficiency?

Answer 36

X-LINKED RECESSIVE genetic disease.

• Associated with ANEMIA because the G6P is especially important in red blood cell metabolism.
• The lack of substrate for NADPH.
• Most individuals with G6PD deficiency are asymptomatic.
• MANIFESTATION – the same as CGD and characterized by the TENDENCY to form granulomas.

Question 37

What are Leukocyte Adhesion Deficiencies (LAD)?

Answer 37

• LAD is caused by mutations in CD18 gene resulting in defective or deficient beta-2 integrin.
• Even without the ongoing infection, NEUTROPHIL COUNT in the blood is about twice the normal level (neutrophilia).
• LAD patients present with a history of RECURRENT INFECTIONS of the oral and genital mucosa, skin, and intestinal and respiratory tracts.
• NEUTROPHILS in patients with LAD are unable to aggregate.
• Neutrophils do not bind to INTERCELLULAR ADHESION molecules on endothelial cells, a step that is necessary for their egress from the vasculature and transport to sites of inflammation.
• As a result, INFECTED FOCI contain few neutrophils and heal slowly, with enlarging borders and dysplastic scars.

LADs are associated with DEFECTIVE MIGRATION of leukocytes (neutrophils) - inability to move to site of infection/injury.

• CLINICAL MANIFESTATIONS: – Delayed detachment of the umbilical cord – Slow wound healing – Severe bacterial infections – Failure to form pus
• PROGNOSIS – the outcome is poor with EARLY DEATH.
• LAD workup involves FLOW CYTOMETRIC ASSESSMENT of the neutrophil adhesion molecules CD11 and CD18.

Question 38

What is Chediak-Higashi Syndrome?

Answer 38

• CHS is an AUTOSOMAL RECESSIVE disorder.
• These PATIENTS become wheelchair-bound and usually die of infection in their early 30s.
• MOLECULAR DEFECT is in structure of neutrophil granule appeared as abnormal giant granules.
• GRANULES do NOT contain cathepsin G and elastase.
• Defects is manifested ABNORMALITIES in chemotaxis and degranulation.
• Prone to recurrent pyogenic GRANULOMAS caused by bacteria infections (staphylococci and streptococci).
• The response to infection is a blunted NEUTROPHILIA and due to delayed diapedesis.
• A BIPHASIC immunodeficiency: » First phase – succesptibility to INFECTIONS. » Second phase – an accelerated LYMPHOPROLIFERATIVE SYNDROME with hepatosplenomegaly and lymphadenopathy.
• DIAGNOSIS: – azurophilic GIANT cytoplasmic INCLUSIONS in blood cells – Partial ALBINISM (defect in growth of melanocytes) – NO NK activity

Question 39

How do you perform a Phagocyte Defect Screen?

Answer 39

Recurrent skin abscesses and/or fungal infections

1. Run CBC/differential.
   - If Leukocytosis, Consider leukocyte adhesion deficiency (LAD)
   - If normal, Consider leukocyte adhesion deficiency (LAD) OR perform Nitroblue tetrazolium dye reduction test
2. Nitroblue tetrazolium dye reduction test- Is oxidase function normal?
   - If abnormal, consider CGD
   - if normal, Chediak-Higashi syndrome (large cytoplasmic granules) or specific defect

Question 40

What is The Clinical Manifestation of Complement Disorders?

Answer 40

• Abnormalities in the EARLY COMPONENTS of the classical pathway: – The C1, C4, and C2 deficiencies are typically manifested as systemic lupus erythematosus-like AUTOIMMUNITY – Associated with recurrent sinopulmonary infections are also seen, especially in C2 deficiency.
• DEFECTS IN C3 result in a clinical phenotype that is INDISTINGUISHABLE from ANTIBODY DEFICIENCIES, although this complement deficiency is markedly less frequent than humoral ab-dependent immunodeficiencies.
• Defects in the LATE COMPONENTS of complement producing defects in the generation of the membrane attack complex (C5-C9) present with: – INCREASED SUSCEPTIBILITY to infections with Neisseria species.

Question 41

What happens in CP Immunodeficiencies?

Answer 41

The CP is responsible for rapid CLEARANCE OF IMMUNE COMPLEXES, apoptotic cells and cell debris from damaged tissues.

• Primary C1 and C4 DEFICIENCY of linked to development of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). – Small complexes are cleared from the circulation when they bind to complement receptors on RBCs – Without complement, the complexes can grow too large to be easily cleared. – These large complexes are no longer soluble, and form deposits in the tissues and become a site of inflammation.
• Primary C2 DEFICIENCY is the most common complement deficiency in Caucasian populations (1 in 10,000 to 1 in 20,000). – found in young children who have recurrent infections with Streptococcus pneumoniae

Question 42

What happens in MAC Deficiencies?

Answer 42

C8 deficiency is inherited in an AUTOSOMAL RECESSIVE pattern.

• Patients with deficiencies of the late complement proteins (C5, C6, C7, C8, and C9) have INCREASED SUSCEPTIBILITY to Neisserial infections.
• Most patients with C8 DEFICIENCY have invasive Neisserial infections.
• THE CAUSE of low levels of C8 may: – inherited deficiencies – acquired deficiencies – due to complement consumption due to chronic complement activation by the ongoing infection.
• DIAGNOSIS: – Absent C8 levels in the presence of normal C3 and C4 values are consistent with a C8 deficiency. – Absent C8 levels in the presence of low C3 and C4 values suggests complement consumption.

Question 43

What is Deficiency in C1-INH?

Answer 43

• HEREDITARY ANGIOEDEMA (HAE) is a disease caused by deficiency of the CP control protein, C1-INH.
• These individuals have RECURRENT SWELLING in the extremities, face, lips, larynx or GI tract.
• THE MECHANISM for production of the swelling involves not the complement enzymes, but a by-product of the kinin-generating pathway.
• It is the production of BRADYKININ through this pathway that is responsible for the tissue permeability changes that cause the swelling.
• Acute TREATMENTS include C1 inhibitor, a replacement therapy (both plasma derived and recombinant products are available).

Question 44

What is Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Answer 44

• PNH is a striking example of the consequences of the FAILURE to regulate the formation of the MAC.
• In this disease, a SOMATIC MUTATION causes a deficiency of glycosylphosphatidylinositol (GPI).
• PNH cells lack all the proteins (~40) linked through the GPI anchor to their cellular membranes.
• Two of the most important GPI anchor proteins are DAF (CD55) and CD59. CD55 and CD59 are COMPLEMENT REGULATORY PROTEINS involved in protecting the red blood cells from the action of complement.
• The most likely CAUSE of intravascular hemolysis in these patients is the increased susceptibility of red cells to complement.

Question 45

How do you perform a Complement Deficiency Screen?

Answer 45

1. Perform Suspected complement deficiency Measure CH50 and AH50
   - If CH50 Normal AH50 Abnormal, Deficiency of component of the Alternative pathway
   - If CH50 Abnormal AH50 Normal OR CH50 Abnormal AH50 Abnormal, Measure C3 and C4 levels
2. Measure Measure C3 and C4 levels
   - If normal or high, measure C1 and C2. if this is low, there is a defect in the classical pathway. if this is normal or high, there is defect in C5-C9
   - If Absent or near absent C4, there is a defect in the classical pathway

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Question 46

What happens in Deficiency of TLRs?

Answer 46

• MyD88 DEFICIENCY is an innate immune deficiency that results in impaired signaling for all TLRs but TLR3 (TLR3 signaling is MyD88-independent).
• MyD88 deficiency leads to abnormally frequent and SEVERE INFECTIONS caused by pyogenic bacteria.
• Patients with MyD88 deficiency have NORMAL RESISTANCE to other common bacteria, viruses, fungi, and parasites.
• Patients characteristically lack FEVERS and elevated levels of ESR/CRP despite active infection.
• During infection, blood levels of PROINFLAMMATORY TNF-α, IL-1, and IL-6 are LOW.
• TLR3 DEFICIENCY is an autosomal dominant disorder which results in INCREASED SUSCEPTIBILITY to HSV encephalitis.