Immunodeficiency (Primary and Secondary Immunodeficiencies) Lecture note

“Immunity” is the word derived from Latin term which gives the meaning “Free From” or “Protects host From”. Immunity protects the host from Infection, Tumors mainly. Immunity can be classified in to two catagories,

• Non specific immunity/Innate Immunity 
• Specific immunity/Adaptive Immunity

Non specific immunity/Innate Immunity-First line of defense

• Intact barriers: skin and mucosa 
• Indigenous flora 
• Secretions: saliva, crevicular fluid and gastric juice 
• Cilliary escalator 
• Urinary flow 
• Macrophages, Monocytes, natural killer cells and Neutrophils 
• Complements and cytokines

Specific immunity/Adaptive Immunity-Second line of defense

More specific

There are two types of specific immunity. They are, Cell mediated and Humoral

Human immune system is a two edged sword.

• If active- It is protective

• If inactive- Immunosuppression

• If overactive- It can cause fatal diseases or chronic illnesses

Immunological Disorders can be classified into 3 distinct categories. 

01.Hypersensitivity

02.Autoimmunity

03.Immunodeficiency

Here on this article, we have described the things regarding Immunodeficiency.

Immunodeficiency

Attenuation of components of specific or non specific immunity can cause immunosuppression.

Definition of Immunocompromised patient

An individual having the immune response attenuated.

It can be due to drugs, radiation, malnutrition or disease.

Immunodeficiency can be classified in to primary and secondary immunodeficiencies

Primary Immunodeficiencies

• APECED (Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy)
• Ataxia telangiectasia
• Bare lymphocyte syndrome
• Bloom syndrome
• Cartilage hair hypoplasia
• Chediak Higashi syndrome
• Chronic granulomatous disease
• Common variable immunodeficiency
• Complement deficiencies
• DiGeorge syndrome/chromosome 22q11.2 deletion syndrome
• Dyskeratosis congenita
• Hyper IgE syndrome
• Hyper IgM syndrome
• IgA deficiency
• IgG subclass deficiency
• IPEX
• Leukocyte adhesion deficiency
• Macrophage activation disorders
• Schwachman’s syndrome
• Severe combined immunodeficiency
• Specific granule deficiency
• Transient hypogammaglobulinemia of infancy
• WHIM
• Wiskott-Aldrich syndrome
• X-linked agammaglobulinemia
• X-linked lymphoproliferative syndrome

 

Features of primary immunodeficiencies

• Frequent infections with typical organisms
• Infections with opportunistic organisms
• Autoimmune diseases + infection history

Screening laboratory studies

These studies will detect most humoral immunodeficiencies and neutrophil/T cell disorders associated with decreased cell numbers.  More specific assays are required for other disorders.

CBC and Differential

Immunoglobulin levels

Antibody responses to immunization

Organisms suggesting an immunodeficiency

Some organisms suggest immunologic dysfunction but the most common presentation of an immunodeficiency is recurrent infections with typical organisms.

• Aspergillus, unusual fungi- Neutrophil disorders
• Burkholderia cepacia- Chronic granulomatous disease
• Cryptosporidia- T cell disorders: HIV, SCID, X-linked hyper IgM
• Enteroviral meningoencephalitis- X-linked agammaglobulinemia
• Mycobacteria (commonly atypical)-Macrophage disorders
• Pneumocystis carinii- T cell disorders: HIV, SCID, X-linked hyper IgM

Immunodeficiencies associated with syndromes

• APECED (Autoimmune polyendocrinopathy with candida and ectodermal dysplasia)
• Ataxia telangiectasia- ataxia at 1-6y, ocular telangiectasias 6-15 y.
• Bloom syndrome-growth failure, sun sensitive dermatosis
• Cartilage hair hypoplasia- metaphyseal dysplasia, sparse hair
• Chediak-Higashi syndrome-pigmentary dilution
• DiGeorge syndrome- cardiac anomaly, hypocalcemia, dysmorphic facies
• Dyskeratosis congenita- IUGR, microcephaly, skin hyperpigmentation
• Griscelli syndrome-pigmentary dilution, CNS disease
• Hyper IgE syndrome- coarse facies, eczema
• Nijmegen breakage syndrome- poor growth, microcephaly
• Omenn’s syndrome- seborrhea, eosinophilia, hepatosplenomegaly, adenopathy
• Schwachman’s syndrome- pancreatic insufficiency, metaphyseal dysplasia
• SCID with multiple intestinal atresias
• Wiskott-Aldrich syndrome- thrombocytopenia, eczema
• X-linked anhidtrotic ectodermal dysplasia with immunodeficiency

                               

Secondary immunodeficiencies

• Chromosomal:  Down’s, Centromeric instability, Chromosome 18 deletions, Turner’s, Fanconi’s anemia
• Metabolic: Uremia, Diabetes, Galactosemia, Glycogen storage diseases, Aminoacidemias
• Protein loss: Protein losing enteropathy, Nephrotic syndrome, Lymphangiectasia, Malnutrition, Burns
• Drugs: Immunosuppressive, Phenytoin, other anti-seizure drugs
• Infections: HIV, EBV, Measles, Influenza, CMV, Leishmania, other chronic infections
• Malignancy: Lymphoma, Thymoma, Solid tumors, Histiocytic disorders
• Miscellaneous: Asplenia, Serious injury

APECED-Autoimmune polynendocrinopathy-candidiasis-ectodermal dysplasia

Gene defect: AIRE, important for thymic tolerance

Features in order of frequency (accumulate with age)

1. Candidiasis
2. Hypoparathyroidism
3. Dental enamel hypoplasia
4. Adrenal failure
5. Ovarian failure
6. Nail dystrophy
7. Ocular keratopathy

Pathophysiology

Aire is a transcription factor which induces the expression of organ-specific genes within the thymus so that thymocytes can become tolerized to those self antigens.

Diagnosis

Clinical with confirmation via mutation analysis (research basis).  Standard laboratory assays of immunologic function are typically normal.

Differential

Chronic candida in infancy is also seen in many of the T cell disorders such as SCID, DiGeorge syndrome, and severe cartilage hair hypoplasia.  Nail dysplasia is seen only in APECED.  As the other autoimmune Features develop, Diagnosis is easier.  Some patients do not have extensive candida in infancy and present with autoimmune disease.  There are forms of chronic mucocutaneous candidiasis which are not due to AIRE mutations.  They are poorly understood and probably represent a heterogeneous group of T cell defects. 

Management

Supportive.  Important to monitor for endocrine dysfunction.

Ataxia telangiectasia

Gene defect: ATM gene, important in signaling DNA repair

Features

• Ataxia beginning about 1-6 years of age
• Ocular and cutaneous telangiectasias beginning about 6-15 years
• Both above Features worsen with age
• Typically fatal in early adulthood
• Progeric changes of skin
• Infections are seen in over half.  Opportunistic infections are uncommon. 
• Poor growth
• Markedly increased risk of malignancy
• Lymphopenia (naïve t cells are particularly diminished)
• Diminished mitogen responses
• Iga deficiency in 50%
• Monoclonal gammopathy
• Laboratory Features seldom correlate with infection pattern
• Karyotype shows increased chromosome breakage
• Elevated alpha fetoprotein
• Heterozygote carriers have an increased risk of malignancy

Pathophysiology

ATM plays a role in the cellular response to radiation damage.  It is critical for cell cycle arrest which allows DNA repair to take place.  Within lymphocytes it plays a role in recombination of Ig and TCR genes.

Diagnosis

Compatible clinical picture with elevation of alpha fetoprotein.  Can confirm with mutation analysis (research basis).

Differential

There is nothing distinctive about the infection pattern.  The combination of ataxia or awkward walking at an early age and infection is highly suggestive.  Essential telangiectasia can mimic the skin findings, while Oculomotor apraxia, and Joubert’s syndrome may mimic the neurologic findings.  Other disorders to consider: Friedreich’s ataxia, Cockayne syndrome, Hartnup disease.

Management

Supportive.  Be alert to lymphoma risk.

Bare lymphocyte syndrome

(MHC class II and MHC class I deficiency)

Gene defect: Multiple.  RFX5, RFXAP and CIITA defects lead to MHC class II deficiency; TAP2 defects lead to MHC class I deficiency.  MHC II deficiency is due to transcription factor defects while MHC I deficiency is due to failure of peptide loading.

Features of MHC II deficiency

• Frequent infections (bacterial and viral)
• Diarrhea
• Progressive liver disease
• Sclerosing cholangitis
• Autoimmune disease
• Absent mhc class ii expression
• Reduced mhc class i expression
• Normal mitogen  responses
• Deficient antigen responses
• Igg, iga, igm reduced usually
• Diminished numbers of cd4 t cells

Features of MHC I deficiency

-Autoimmune disease

-Bronchiectasis

-Nasal polyposis

-Cutaneous inflammatory disorders

-Normal numbers of T cells

Pathophysiology

MHC class II is required for positive selection of CD4 T cells and recognition of extracellular antigens.  MHC class I is required for selection of CD8 T cells and recognition of intracellular antigens.  Thus, failure to defend against pathogens and failure to recognize self are the major findings.

Diagnosis

Measure DR and MHC class I expression by flow cytometry.

Differential

The MHC II deficient patients often present in infancy and have Features similar to SCID or to mild SCID variants.  Autoimmune disease can cause some diagnostic confusion.  The MHC I deficient individuals have no specific clinical Features other than diminished expression of MHC class I

Management

BMT is optimal for MHC II deficiency.  MHC I deficiency has been treated with supportive Management.

Bloom syndrome

Gene defect: BLM is a helicase involved in Holliday junction branch migration.  Defects lead to hyper-recombination and genetic instability.

Features

• IUGR and poor growth
• Poor feeding
• Sun-sensitive butterfly rash
• Approximately half have recurrent sinopulmonary infections
• Diabetes and cancer with increasing age
• Mild hypogammaglobulinemia
• Increased sister chromatid exchange
• Increased chromosome gaps, quadriradials
• No sperm in semen
• Endocrine labs are normal
• Reduced life expectancy

Pathophysiology

The mechanism involved in the immunodeficiency is not fully understood.  BLM’s role in recombination may lead to poor recombination of Ig and TCR genes.

Diagnosis

Ashkenazi Jewish people have a founder mutation and direct mutation analysis is possible.  For others, demonstration of increased sister chromatid exchange allows the Diagnosis.

Differential

Werner’s syndrome, Russell-Silver dwarfism, primordial dwarfism, SLE, erythropoietic protoporphyria, Rothmund-Thompson syndrome, Cockayne syndrome

Management

Supportive.  IVIG seldom indicated but aggressive Management of infections is appropriate. Surveillance for malignancies.  Treatment of malignancies requires dosage and drug adaptations.  Cord blood storage from siblings could be considered.

Cartilage hair hypoplasia

Gene defect:  RNase MRP which cleaves nucleolar pre-mRNAs and mitochondrial RNA

Features

• Metaphyseal chonrodysplasia
• Hair hypoplasia
• Limited extension of elbows
• Ligamentous laxity
• Increase in infections in half
• Anemia
• Hirschprung disease
• Lymphopenia, neutropenia variable
• Diminished mitogen responses
• Diminished immunoglobulins
• Increased risk of malignancy
• Opportunistic infections and fatal viral infections rarely
• Founder mutations in amish and finland

Pathophysiology

The mechanism by which defects in RNase MRP lead to cartilage hair hypoplasia is not known.

Diagnosis

Few other immunodeficiencies are associated specifically with metaphyseal chondrodysplasia.  The Diagnosis is usually clinical.

Differential

Schimke immuno-osseous dysplasia is a spondyloepiphyseal dysplasia associated with renal disease and a T cell defect.  ADA deficiency has metaphyseal changes but the patients do not exhibit dwarfism.

Management

Most patients require only supportive care and precautions against varicella.  A minority require IVIG.  Rare patients have a serious immunodeficiency and require bone marrow transplantation. 

Chediak Higashi syndrome

Gene defect:  The LYST gene, recently renamed CHS1 is important for movement of lysosomes,

Features

• Patients with Chediak Higashi syndrome typically manifest recurrent infections early and then develop a hemophagocytic process, once termed the accelerated phase. 
• Partial oculocutaneous albinism
• Light or silvery hair
• Mild bleeding diathesis
• Milder variants may present with peripheral neuropathy
• Recurrent bacterial infections
• Giant inclusions in pmn are diagnostic
• Decreased nk function
• Diminished pmn chemotaxis
• Ct of the head shows diffuse atrophy

CHS hemophagocytic process

• Fever
• Jaundice
• Pancytopenia
• Hypertriglyceridemia
• Low fibrinogen
• Elevated ldh and ferritin
• Cns disease

Pathophysiology

Cytotoxic T cells and NK cells cannot mobilize their cytotoxic granules effectively and kill.  When infection (often a herpes family infection) activates the cytotoxic response, T cells and macrophages become activated.  When the infection is not cleared, the process escalates.

Diagnosis

The demonstration of giant inclusions in PMN is diagnostic.  Hair samples and skin biopsies can also be used to demonstrate abnormal melanin transfer.

Differential

Griscelli disease has two forms, both of which can mimic Chediak Higashi syndrome. Primary hemophagocytic lymphohistiocytosis.  Lymphoma.

Management

85% of patients will develop hemophagocytosis.  The success of BMT is higher when performed prior to the development of hemophagocytosis.  Management until the BMT is performed or for mild variants would include prophylactic antibiotics and dental prophylaxis for gingivitis.

Chronic granulomatous disease (CGD)

Gene defect. Multiple. The X-linked form is due to defects in CYBB which encodes the gp91 phox component of NADPH oxidase.  3 AR forms are due to defects in NCF1, NCF2, or CYBA which are all also due to defects in components of NADPH oxidase.  One family has been described with defects in RAC2 which is a protein which regulates NADPH oxidase.

Features

-recurrent infections: often pneumonia or abscesses

-organisms are often Staphylococcus, Aspergillus, gram negative bacteria or unusual organisms

-Crohn’s disease

-discoid lupus

Pathophysiology

NADPH oxidase is responsible for superoxide production which is then converted to hydrogen peroxide.  The organisms to which CGD patients are particularly susceptible are catalase positive organisms which degrade ambient hydrogen peroxide.  Not all catalase positive organisms are equally problematic and another factor regulated by NADPH oxidase is potassium flux across the membrane.  This is important for the release of cationic granule proteins such as elastase and cathepsin.

Diagnosis

The Diagnosis is established through the use of dyes which measure reactive oxygen production.  The most common ones are nitroblue tetrazolium, rhodamine, and dichlorofluorescein.  The fluorescent dyes are more sensitive.  Carrier detection of the X-linked form is possible with the fluorescent dyes, however, mutation analysis is more accurate.

Differential

Specific granule deficiency, Hyper IgE syndrome, neutropenia, Crohn’s disease, histiocytic disorders.

Management

There is little consensus on Management other than the use of prophylactic co-trimoxazole.  Itraconazole has shown benefit recently as a fungal prophylactic and gamma interferon has been shown to reduce hospitalization frequency.  Acute infections require very aggressive Management with surgical debridement of infection.  Some patients have been treated successfully with intralesional antibiotics and interferon.  The granulomatous complications have been treated with steroids.  BMT is considered experimental.

Common variable immunodeficiency (CVID)

Gene defect: multigenic.  Susceptibility locus in the MHC region.

Features

• Peak age of onset is 15-35 years
• Infantile onset patients have a worse prognosis and probably represent a distinct clinical entity
• Recurrent sinopulmonary infections
• Various autoimmune diseases
• Nodular lymphoid hyperplasia
• Sarcoid like granulomatous infiltrates
• Increased risk of malignancy
• Hypogammaglobulinemia
• Poor response to immunization
• Variable t cell defects

Pathophysiology

CVID is a disease of attrition with gradual fading of immunoglobulin production.  The genetic susceptibility is poorly understood but there is roughly a 10% risk of a primary relative developing the disease.  This disease is probably heterogeneous with some patients have abnormalities of T cells and others having primary B cell defects.

Diagnosis

Hypogammaglobulinemia in the absence of a known cause and poor responses to immunizations.

Differential

Drug-induced hypogammaglobulinemia, protein losing enteropathy, thymoma, SCID, XLA, transient hypogammaglobulinemia of infancy

Management

Monthly IVIG.  Some patients may benefit from prophylactic antibiotics.  Autoimmune disease is treated as usual.

Complement deficiencies

Gene defect:  Defects in each of the genes encoding each complement component except factor b have been described

Features of C1, C2, C4 deficiencies

Recurrent bacterial infections

Sle

Features of C3 deficiency

Very severe recurrent bacterial infections

Glomerulonephritis

Features of FD, C5, C6, C7, C8, C9, Properdin deficiencies

-recurrent meningococcal disease or meningococcal infection with unusual serotype

Pathophysiology

Complement opsonizes bacteria and facilitates their uptake.  It is also important for the clearance of immune complexes and apoptotic cells.

Diagnosis

CH50 results will usually be near zero for all but C9, FD, and properdin deficiencies.  AH50 can be used to measure the alternative pathway function.  Specific assays for individual components are available.

Differential

Hypogammaglobulinemia, SLE with complement consumption, serum sickness.

Management

Supportive.  Prophylactic antibiotics can be helpful in some cases.  C2 deficient patients with SLE have been successfully treated with plasma or C2 infusions in Europe.

DiGeorge syndrome/ chromosome 22q11.2 deletion syndrome

Gene defect

About 95% of patients with DiGeorge syndrome, defined by cardiac anomaly, hypocalcemia and thymic hypoplasia, have a microdeletion of chromosome 22q11.2.  The remainder have deletions or mutations on chromosome 10 or have an unknown genetic defect.

Features

• Cardiac anomaly
• Feeding difficulties
• Hypocalcemia
• Diminished t cell numbers
• Speech delay
• Palatal weakness or cleft
• Renal anomalies
• Skeletal anomalies
• Autoimmune disease

Pathophysiology

There are 22 genes within the commonly deleted region.  The Tbx1 gene is thought to be the most important for parathyroid, thymus, and cardiac development.  Other genes may contribute to other phenotypic Features.

Diagnosis

DiGeorge syndrome is diagnosed clinically.  The deletion is detected by fluorescence in situ hybridization of the deleted region but is not required for the Diagnosis of DiGeorge syndrome.

Differential

CHARGE syndrome, Opitz GBBB syndrome.  Most cases of CTAF and velocardiofacial syndrome are due to the deletion.

Management

Supportive.  The immunodeficiency may improve in the first year of life.  When the immunodeficiency is severe, thymic transplantation or fully matched sibling BMT is indicated.  Hypocalcemia requires calcium and vitamin D supplementation but also usually improves in the first year of life.  The cardiac anomaly is treated as usual.  Adnoidectomy is contraindicated.

Dyskeratosis congenita

Gene defect

Mutations in DKC1 are responsible for the X-linked form which accounts for approximately 80%.  Mutations in hTR cause the autosomal recessive form.  Both gene products are involved in maintenance of telomeres.

Features

• IUGR
• Microcephaly
• Progressive skin hyperpigmentation
• Esophageal stricture
• Dysplastic nails
• Sparse hair
• Colitis
• Leukoplakia
• Progressive pancytopenia
• Hypogammaglobulinemia
• Variable t cell deficiency
• Increased risk of malignancy

Pathophysiology

Highly proliferative tissues undergo replicative senescence and cell death when the telomeres reach a critically short length.

Diagnosis

Clinical characteristics are generally sufficient for the Diagnosis.  Mutation analysis is available on a research basis.  One other syndrome has been sporadically associated with mutations in DKC1 or hTR: Hoyeraal-Hreidarsson syndrome

Differential

Fanconi’s anemia, inflammatory bowel disease, APECED, ectodermal dysplasia.

Management

Supportive.  Rare patients require IVIG.  Many will eventually require erythropoietin and/or GCSF.  BMT has been used for marrow failure and malignancy but requires adjustment of conditioning and does treat all aspects of the disease.

Hyper IgE syndrome

Gene defect

Unknown. Autosomal dominant.

Features

• Coarse facial Features
• Recurrent staphylococcal abscesses
• Abscesses lack hallmarks of inflammation
• Pulmonary infections lead to emphasematous changes
• Scoliosis
• Delayed shedding of primaryteeth
• Osteopenia
• Markedly elevated ige
• Variable mild defects in igg function
• Wide spectrum of severity

Pathophysiology

Unknown

Diagnosis

Markedly elevated IgE level in association with compatible clinical findings.  The IgE level will fall somewhat with age and there have been some mild variants ascertained through family studies.

Differential

CGD, Staphylococcal carriage, specific granule deficiency, eczema, Omenn’s syndrome, Wiskott-Aldrich syndrome, HIV.

Management

Prophylactic antibiotics are routinely used to prevent Staphylococcal infection.  IVIG has been used infrequently.  Pulmonary toilet is important.  Infections must be treated aggressively.  Staphylococcus is the most frequent organism, but opportunistic infections should be considered.  Protection from fracture.

Hyper IgM syndrome

Gene defect

X-linked form is most common and is due to mutations in CD40L (TNFSF5).  Three autosomal recessive forms are known and the gene defects are in CD40, AID, and UNG.  Defects in Ikkgamma (ectodermal dysplasia with immunodeficiency) are sometimes classified as hyper IgM patients but only a subset have elevated IgM.  AID defects are the most common of the AR forms.  All four gene products are required for B cell class switch recombination.

Features

• Sinopulmonary infections begin in infancy
• Pneumocystis carinii (xl form)
• Neutropenia episodically
• Autoimmune disease
• Low igg
• Normal to elevated igm
• Igm is markedly elevated with aid mutations
• Normal numbers of t and b cells
• Cryptosporidia (xl form)
• Cholangitis or biliary carcinoma
• Increased frequency of malignancy

Pathophysiology

All four known genes encode proteins which are important for class switch recombination of B cells.  CD40L on T cells signals the B cell via CD40 in the germinal center.  Intracellular signaling involves activation of NFkB via IKK gamma.  AID deaminates dC DNA residues which are subsequently removed by UNG, leading to breaks which are required for class witch recombination.

Diagnosis

Normal or elevated IgM with very low IgG, IgA is typical of the XL form.  T cell numbers and mitogen responses are normal with poor T cell responses to antigen stimulation.  The other forms are less well characterized but are associated with normal T cells and absence of opportunistic infections usually.  There may be some limited production of IgG.  Mutation analysis is available on a research basis.

Differential

XLA, CVID, SCID, HIV

Management

Monthly IVIG is required.  The XL form has a limited life expectancy due to the high rate of malignancy.  In some centers BMT is offered.  Autoimmune disease is managed as for any other patient.  Prophylactic antibiotics may be beneficial.

IgA deficiency

Gene defect

Unknown.  Polygenic pattern of inheritance.  Runs in families with CVID.

Features

• Most common in Caucasian: 1:500
• Most are asymptomatic
• More likely to have symptoms if igg subclasses are abnormal
• Increased frequency of bacterial infections of mucous membranes
• Increased risk of allergies
• Increased risk of autoimmune disease
• Risk of transfusion reaction increased
• Iga deficiency can be caused by a fairly large number of drugs, particularly anti-seizure drugs and rheumatologic drugs
• Transient iga deficiency has been described with several types of infections including EBV, congenital rubella, and toxoplasma

Pathophysiology

IgA is the most abundant immunoglobulin on the surface of mucous membranes.  It is important for host defense at these sites but IgG may compensate somewhat.  Thus IgA deficiency is a mild immunodeficiency.

Diagnosis

IgA less than 5mg/dl in a patient over the age of 2y.

Differential

CVID, ataxia telangiectasia, Wiskott-Aldrich syndrome.  Drug induced IgA deficiency is often not reversible.

IgG subclass deficiency

Gene defect

Unkown.

Features

• There is a lack of consensus regarding the definition of this disorder or even whether it represents a distinct primary immunodeficiency
• Absence or markedly diminished igg1, igg2, or igg3
• Igg4 is absent in many normal children
• Recurrent upper respiratory tract infections
• Patients with deletions of one of the heavy chain genes for igg are generally healthy, thus absent production from a normal gene implies dysregulation
• IgG2 plus IgA deficiency is associated with more significant infections
• IgG1 subclass deficiency is usually associated with diminished total IgG, the others are not
• Aberrant responses to immunizations in addition to a subclass deficiency may be a form fruste of CVID
• T cell numbers and function are normal

Pathophysiology

The mechanisms underlying IgG subclass deficiencies is unknown

Diagnosis

IgG subclass determination in a person over the age of 2y which demonstrates a single subclass which is markedly depressed with preservation of IgM and other subclass levels.

Differential

CVID

Management

Many patients will do well with prophylactic antibiotics or removal from high exposure situations.  The more severe the defect, the more likely the patient will require IVIG.

IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)

Gene defect

Scurfin protein is encoded by the FOXP3 gene.  This gene is critical for the development of T cells with tolerizing function

Features

• Very early onset diarrhea
• Small bowel villous atrophy, mucosal ulcerations
• Early onset diabetes
• Hypothyroidism
• Often fatal
• Other autoimmune disorders seen
• Eczema
• Eosinophilia
• Hypogammaglobulinemia (may be loss)
• Elevated ige
• Antibodies to enterocytes
• Global t cell activation and increased mitogen responses
• Diminished cd4/cd25 t cells
• Some mild variants have been described

Pathophysiology

The FOXP3 gene encodes a transcription factor.  Most mutations are in the DNA-binding domain.  Lack of FOXP3 leads to an inability to produce CD4/CD25 T cells which act as regulatory T cells and prevent autoimmunity.

Diagnosis

Compatible clinical Features and markedly diminished CD4/CD25 T cells or other characteristic lab finding.  Mutation analysis is available on a research basis.

Differential

Infantile IBD, SCID, APECED, celiac disease

Management

Immunosuppression with FK506 or cyclosporin has been of benefit but has not led to improvement in survival.  BMT has been attempted with infrequent successes.

Leukocyte adhesion deficiency (LAD)

Gene defect

Multiple.  LAD I is the most common type and is due to mutations in the gene encoding CD18 or beta2 integrin common subunit (ITGB2).  LAD II (aka congenital disorder of glycosylation IIc) is due to mutations in the GDP-L-fucose transporter.  LAD I variants have unknown mutations in which beta2 integrin expression is normal but function is defective.

Features

• Elevated resting neutrophil counts
• Recurrent infections with poor pus formation
• Rapidly progressive, necrotic skin infections
• Spontaneous peritonitis
• Gingivits
• Frequent sepsis
• 10% have delayed separation of the umbilical cord
• Diminished dth in lad i and lad i variant
• Normal immunoglobulins
• Lad ii patients have developmental delay and dysmorphic Features
• Lad ii patients have the bombay blood group

Pathophysiology

The beta2 integrins regulate firm adhesion to the endothelial cell wall and the initial stages of emigration.  The fucosylated selectins which are defective in LAD II are important for rolling.  This defect is milder than the defect in integrins because in conditions of slow flow, adhesion can still occur.

Diagnosis

LAD I is diagnosed by flow cytometry for CD11 or CD18 expression on neutrophils.  Levels of 0-25% are typical.  LAD II is diagnosed through the finding of compatible clinical Features and the Bombay blood group.  LAD I variant patients have been diagnosed in research labs capable of measuring adhesive function.

Differential

CGD, necrotizing fasciitis, inflammatory bowel disease.

Management

BMT is indicated for the most severely affected.  Milder cases of LAD I have been treated with prophylactic antibiotics.  LAD II has been treated successfully with fucose.  Each infection must be treated very aggressively and WBC transfusions are often required.  Wound healing can be poor and GM-CSF topically may help.

Macrophage activation disorders

Gene defect

Multiple.  Both receptor chains for gamma-interferon (IFNGRI, IFNGRII), STAT1, IL-12p40, IL-12Rbeta1.  All are important in activating the intracellular killing pathway of macrophages.  Defects in IKKgamma (ectodermal dysplasia with immunodeficiency) are also sometimes placed in this category.

Features

• Atypical mycobacterial infection is the hallmark
• Listeria
• Salmonella
• Rare herpes family infections
• Standard assays of immunologic function are normal

Pathophysiology

TNF alpha and interferon-gamma are the major cytokine mediators of granuloma formation and containment of intracellular pathogens.  In addition, they regulate intracellular killing.  IL-12 activates the macrophage and also promotes intracellular killing.

Diagnosis

Currently, the Diagnosis rests on the demonstration of impaired responses to stimuli in vitro performed in a research lab.  IKK gamma mutations analysis is available commercially as part of incontinentia pigmenti mutation testing.

Differential

Histiocytic syndromes, SCID, HIV, CGD.

Management

Patients require very aggressive and prolonged treatment of mycobacterial disease and may benefit from prophylaxis.  Salmonella must similarly be treated aggressively and may also require prophylaxis to prevent recurrence.  Patients with forms other than complete null mutations of interferon-gamma receptor benefit from SQ interferon-gamma adminstration.

Schwachman’s syndrome

Gene defect

Unknown

Features

• Malabsorption beginning in infancy
• Neutropenia
• Staphylococcus and gram negative organisms dominate
• Poor neutrophil chemotaxis
• Anemia and thrombocytopenia 20%
• Metaphyseal dysostosis
• Short stature
• Increased risk of leukemia
• Aplastic anemia/myelodysplasia

Pathophysiology

The cause of these diverse Features is unknown

Diagnosis

Compatible clinical Features. 

Differential

Dyskeratosis congenita, Fanconi’s anemia, Dubowitz syndrome, cystic fibrosis.

Management

Oral enzymes, vitamin supplementation, erythropoietin and GCSF cautiously due to leukemia risk.  BMT is occasionally performed.

Severe combined immunodeficiency (SCID)

Gene defect

Multiple.  X-linked SCID is the most common and is due to defects in the common gamma chain of several cytokine receptors.  Adenosine deaminase deficiency and Jak 3 deficiency are the next most common.  IL-7 receptor, Artemis, RAG 1/2, PNP, ZAP 70, and reticular dysgenesis are uncommon causes of SCID.  There are several other gene defects that have been identified in single kindreds.

Features

• Absent lymphoid tissue
• Hypogammaglobulinemia
• Impaired t cell function
• Absolute lymphocyte count is usually <2800
• Unable to clear viral infections
• Candida
• Bacterial infections
• Pneumocystis carinii
• Diarrhea
• Small thymic volume
• Presentation by 6m usually

Pathophysiology

All of the SCID defects lead to dysfunctional T cells and many types of SCID are associated with impaired production of T cells.  T cells defend against viral infections and regulate production of antibodies.

Diagnosis

Demonstration of markedly diminished T cells or failure to respond to mitogens.  SCID patients are often categorized according to which lymphocytes are being produced normally ie, T-, B-, NK+.  Mutation analysis or flow cytometry is offered for Diagnosis on a research basis.

Differential

HIV, XLA, CGD, IPEX, cystic fibrosis, Hyper IgM syndrome, APECED

Management

BMT is standard of care for the treatment of SCID.  Gene therapy and PEG-ADA are available on a research basis for ADA deficiency and X-SCID.  While awaiting BMT, patients should be in isolation, on PCP prophylaxis and IVIG.  Infections and suspected infections should be treated aggressively.

Specific granule deficiency

Gene defect

CCAAT/enhancer binding protein epsilon.  This is a transcription factor required for myelopoiesis.

Features

• Rare disorder
• Neutrophils lack secondary granules
• Poor chemotaxis
• Abnormal neutrophil nuclei (bilobed)
• Aspergillus infections
• Frequent staphylococcal infections
• Pseudomonas infections

Pathophysiology

Lack of CCAAT/enhancer binding protein epsilon results in a partial maturational block at the promyelocyte stage.  Secondary granules fail to form as do gelatinase containing granules.  Eosinophils are also abnormal.

Diagnosis

Distinctive ground glass appearance of neutrophils with bilobed nuclei.

Differential

CGD, LAD, Hyper IgE syndrome.

Management

Little information.  Most patients have been treated with prophylactic antibiotics and aggressive treatment of recognized infections.

Transient hypogammaglobulinemia of infancy

Gene defect

Unknown. 

Features

• Diminished total igg
• Preserved ability to make antibodies to immunogens
• Iga may be diminished or normal
• Normal B/T cell numbers
• Onset of symptoms approximately 6 months of age
• Recurrent sinopulmonary infections
• Can be seen with early infantile exposure to steroids
• May run in families or families with other immunodeficiencies

Pathophysiology

Thought to represent developmental delay of immunoglobulin production.

Diagnosis

Low IgG with intact titers to immunogens.  Observe a gradual rise over months to years.  Usually normalizes by 2-4 years of age although rare patients have taken longer.  Failure to improve should be investigated with re-immunization to document continued ability to produce functional antibody.

Differential

Infantile CVID, XLA, Hyper IgM.

Management

Observation is appropriate when the IgG is following the expected rise.  If the IgG is quite low and persists and the Diagnosis is uncertain, a short course of IVIG followed by retesting could be warranted.

Wiskott-Aldrich syndrome

Gene defect

The WASP gene on the X-chromosome encodes a protein which acts as a scaffold for signaling molecules.

Features

• Throbocytopenia with small platelets
• Eczema
• Recurrent infections of skin, respiratory tract
• Bacterial infections are often with encapsulated bacteria
• Infrequent opportunistic infections
• Increased risk of malignancy
• Autoimmune disease is frequent
• Normal igg with low igm, high iga
• Eosinophilia
• Cd8 t cells are low in some patients
• T cell function ranges from normal to low

Pathophysiology

WASP is important for T cell polarization towards antigen and myeloid cell polarization towards a pathogen or chemotactic gradient. 

Diagnosis

A compatible clinical picture with thrombocytopenia and small platelets is the most common diagnostic strategy.  A minority of patients have thrombocytopenia and mild or no immunodeficiency.  They have a better prognosis.  Mutation analysis is available on a research basis.

Differential

Neonatal alloimmune thrombocytopenia, ITP, Omenn’s syndrome.

Management

Severely affected boys with a matched sibling donor are often treated with BMT.  Success with haploidentical or unrelated matched donors has not been as good.  Mild to moderately affected boys are often treated with antibiotic prophylaxis, IVIG, or simply observation.  Younger children are at risk for intracranial hemorrhage.  Older children should be restricted from contact sports or high risk sports.  The eczema responds to topical treatment.  Acute bleeding episodes are often difficult to manage and may follow an illness and present as ITP superimposed on their baseline thrombocytopenia.  Steroids, IVIG, and splenectomy have all been used successfully although splenectomy carries an even higher risk of post-splenectomy sepsis in these patients.

X-linked agammaglobulinemia (XLA)

Gene defect

Btk is the signaling molecule which is defective in XLA.

Features

• Typical age of onset is prior to 12m
• Sinopulmonary infections with typical organisms
• Diarrhea
• Sepsis and abscesses
• Enteroviral encephalitis or dermatomyositis
• Absent tonsillar/adnoid tissue
• Extremely low b cell numbers
• Pathology shows absent plasma cells

Pathophysiology

Btk is required for the progression of B cell development beginning at the pro-B cell stage.  Its absence leads to impaired development of B cells and thus, very little immunoglobulin.

Diagnosis

Hypogammaglobulinemia is usually extreme but mild variants have been reported.  Demonstration of extremely low peripheral B cell numbers is usually the diagnostic test of choice.  Diagnosis and carrier status can be determined by flow cytometry for monocyte Btk levels (research).

Differential

Infantile common variable immunodeficiency, Hyper IgM, SCID, HIV, transient hypogammaglobulinemia of infancy.

Management

Monthly infusions of IVIG to maintain the trough IgG above 500mg/dl.  Prophylactic antibiotics are indicated in some cases.  Overall prognosis is good.

X-linked lymphoproliferative syndrome

Gene defect

SH2D1A is expressed in lymphocytes and regulates the function of cell surface SLAM, 2B4 and NTB-A. 

Features

• 2/3 of patients develop fatal infectious mononucleosis (median age is 3y)
• 1/3 of patients develop dysgammaglobulinemia (median age is 9 y)
• 1/3 develop lymphoma (median age is 6y)
• Aplastic anemia, vasculitis
• Dysgammglobulinemia and lymphoma can occur in ebv seronegative individuals
• Sequential Features common for survivors

Pathophysiology

T-B cell communication is compromised by the dysfunction of signaling from the cell surface receptors which can lead to chronic T cell activation.  NK cells from XLP patients fail to kill EBV infected targets.

Diagnosis

Clinical:  2 or more maternally related males with a characteristic phenotype following EBV infection.  Can confirm the Diagnosis by mutation analysis or Western blot detection of protein (research).  It is optimal to detect EBV via PCR rather than serologic methods.

Differential

Sporadic fatal infectious mononucleosis, familial hemophagocytic lymphohistiocytosis, common variable immunodeficiency, XLA, Hyper IgM.

Management

BMT prior to EBV infection appears to offer the best opportunity for full life expectancy.  Non-myeloablative BMT has been performed.  Acute hemophagocytosis due to EBV is best treated with etoposide, steroids and cyclosporine.  Lymphoma is treated with standard Management but has a propensity to recur and may have a different clonotype.  Dysgammaglobulinemia is treated with IVIG. 

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