“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)
- Candidiasis
- Hypoparathyroidism
- Dental enamel hypoplasia
- Adrenal failure
- Ovarian failure
- Nail dystrophy
- 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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