Primary combined antibody and cellular immunodeficiencies

1. Primary Combined Antibody and
Cellular Immunodeficiencies
CHAIRPERSON-DR BALAJI.M.D
MODERATOR-DR.VEERABHADRA
PRESENTOR-SAI HARI

2. CASE NO.1
• A 6 years old girl presented with repeated episodes of respiratory
infections since the age of 2 years.
• Frequency of such attacks were variable. However, minimum two
such episodes were noticed per month.
• There was no specific time of occurrence or any weather predilection.
• There was no history of loose motions, skin lesions, anorexia, weight
loss, contact with patient suffering from Tuberculosis or family history
of asthma or allergy.
• Response to antibiotics and bronchodilators was temporary at best.
She received AntiTuberculosis treatment for 9 months .

3. • On examination, she was vitally stable with grade 1 clubbing. Examination
of chest revealed vesicular breathing on right side of the chest.
• Bronchial breathing was appreciated over left middle part of chest.
• Rest of the systemic examination was unremarkable.
• Investigations revealed complete blood counts (CBCs) within normal range
with normal total and differential leukocyte counts.
• On chest x-ray, patchy shadowing and atelectasis were reported in right
hilar region.
• CT chest revealed hyperventilated lungs and bronchiectasis with patchy
consolidation/atelectasis.

4. • Serum immunoglobulin levels showed slightly raised Immunoglobulin
E (IgE) levels while Immunoglobulin G (IgG) and Immunoglobulin A
(IgA) levels were within the age specific reference range.
• DELTA F508 mutation was tested and found negative for cystic
fibrosis.
• The patient was referred to Immunology Department of Armed
Forces Institute of Pathology (AFIP), Rawalpindi for further evaluation
and workup.
• Her Erythrocyte Sedimentation Rate (ESR) was 46 mm at 1st hour.

5. • The level of C reactive protein was raised at 12mg/l. Serum IgG and IgM
were within the age specific reference range, while IgA was undetectable.
The level of Serum IgE were raised to 95 IU/ml.
• Functional antibodies against Candida and E coli were positive. Anti
aspergillus antibodies were negative.
• Anti Diphtheria and Anti Tetanus antibodies, before (0.12 IU/ml and 0.02
IU/ml respectively) and after the immunisation (0.42 IU/ml and 0.10 IU/ml
respectively), showed adequate response.
• Lymphocyte subset analysis of peripheral blood was performed and was
repeated after one month.
• Both analyses revealed a decrease in percentage and absolute number of
total lymphocytes.

6. • CD19+ B lymphocytes were virtually absent from the peripheral
blood with decrease in the absolute number of total CD3+ T and
CD16 CD56+ NK cells.

8. DIAGNOSIS ?
• WISKOTT ALDRICH SYNDROME
• Autoimmune lymphoproliferative syndrome
• IMMUNE-DYSREGULATION, POLYENDOCRINOPATHY, ENTEROPATHY, X-
LINKED SYNDROME
• Severe Combined Immunodeficiency (SCID)
• ADA DEFICIENCY
• ATAXIA-TELANGIECTASIA
• Autosomal Recessive Hyper-IgE Syndrome
• Autosomal Dominant Hyper-IgE Syndrome

10. • Results of the second analysis showed deterioration in the lymphocyte count as
compared to the first one, which provided the first clue to possible ADA
deficiency.
• Because of limitations of diagnostic modalities in Pakistan, blood specimen of
patient was sent to Duke University Medical Center, North Carolina, where ADA
(adenosine deaminase), PNP (purine nucleoside phosphorylase), dAXP (total
deoxyadenosine nucleotide) and %dAXP (dAXP/AXP+dAXP) levels were tested.
• Results were interpreted as deficient ADA activity with normal PNP activity; dAXP
(total deoxyadenosine nucleotide) was elevated. She was found to be
homozygous for a missense mutation (R156H in exon 5; a delayed onset
phenotype of ADA deficient SCID).
• The whole data was consistent with Late Onset/Partial ADA-Deficient Severe
Combined Immunodeficiency.
• The patient responded reasonably well to antimicrobial and antifungal therapy.

11. • Disease prognosis was explained to parents with counseling regarding
possible benefits of ADA replacement therapy.
• Gene replacement therapy was explored but not offered to this
patient as it is indicated for patients with complete ADA deficiency.
• Bone marrow transplant from HLA identical donor was also discussed
and possible hazards of bone marrow transplant such as infections,
graft versus host disease and lack of engraftment were told.
• The family, due to stable state of the patient, decided not to go for
this option at present.

12. Severe Combined Immunodeficiency (SCID)
• The syndromes of SCID are caused by diverse genetic mutations that
lead to absence of all adaptive immune functions and, in some, a lack
of B cells and natural killer (NK) cells.
• Patients with this group of disorders have the most severe
immunodeficiency.
• PATHOGENESIS -SCID results from mutations in any 1 of at least 13
known genes that encode components of the immune system crucial
for lymphoid cell development
• All patients with SCID have very small thymuses (<1 g) that usually
fail to descend from the neck, contain no thymocytes, and lack
corticomedullary distinction or Hassall corpuscles.

14. • Severe Combined Immunodeficiency (SCID) group includes primary
immunodeficiencies that lead to severe life threatening infections and
are usually fatal in infancy.
• SCID is rare with an incidence of about 1 in 40,000-100,000 live
births.
• Adenosine deaminase (ADA) deficiency is an inherited condition that
accounts for about 12% of SCID variants.
• Clinical onset may be delayed by 5-8 years in 10-15% of cases.

15. • The thymic epithelium appears histologically normal.
• Both the follicular and paracortical areas of the spleen are depleted of
lymphocytes.
• Lymph nodes, tonsils, adenoids, and Peyer patches are absent or
extremely underdeveloped.

16. CLINICAL MANIFESTATIONS
• Severe Combined Immunodeficiency is the term applied to a group of rare
genetic disorders characterised by defective or absent T and B cell
functions.
• Patients usually present in first 6 months of life with
respiratory/gastrointestinal tract infections and failure to thrive.
• Affected infants present within the 1st few months of life with recurrent
or persistent diarrhea, pneumonia, otitis media, sepsis, and cutaneous
infections.
• Growth may appear normal initially, but extreme wasting usually ensues
after diarrhea and infections begin.
• Persistent infections with opportunistic organisms including Candida
albicans, Pneumocystis jiroveci, parainfluenza 3 virus, adenovirus etc may
lead to death.

17. • Affected infants also lack the ability to reject foreign tissue and are
therefore at risk for severe or fatal graft-versus host disease (GVHD)
from T lymphocytes in non irradiated blood products or in allogeneic
stem cell transplants(ASCT) or less severe GVHD from maternal
immunocompetent T cells that crossed the placenta while the infant
was in utero
• Because all molecular types of SCID lack T cells, the profound T-cell
lymphopenia can be detected on dried blood spots routinely
collected from heel sticks shortly after birth for the purpose of
newborn screening.

18. • These infants also have an absence of lymphocyte proliferative
responses to mitogens, antigens, and allogeneic cells in vitro.
• Patients with adenosine deaminase (ADA) deficiency have the lowest
absolute lymphocyte counts, usually <500/mm3, but infants with all
molecular types of SCID are lymphopenic because they lack T cells
(normally accounting for 70% of circulating lymphocytes).
• Serum immunoglobulin concentrations are low or absent, and no
antibodies are formed after immunizations.
• T cells are extremely low or absent in all types; when detected, in
most cases they are transplacentally derived maternal T cells.

19. TREATMENT
• SCID is a true pediatric emergency.
• Unless immunologic reconstitution is achieved through stem cell
transplantation or gene therapy, death usually occurs during the 1st
yr of life and almost invariably before 2 yr of age.
• If diagnosed at birth or within the 1st 3.5 months of life, >92% of
cases can be treated successfully with human leukocyte antigen
(HLA)-identical or T-cell–depleted haploidentical (half matched)
parental hematopoietic stem cell transplantation without the need
for pretransplant chemoablation or posttransplant GVHD prophylaxis.

20. • ADA-deficient SCID and X-linked SCID have been treated successfully
with somatic gene therapy .
• ADA-deficient SCID can also be treated with repeated injections of
polyethylene glycol modified bovine ADA (PEG-ADA), although the
immune reconstitution achieved is not as good as with stem cell or
gene therapy.

21. Adenosine Deaminase Deficiency
• An absence of the enzyme ADA is observed in approximately 15% of
patients, the second most common form of SCID, resulting from various
point and deletional mutations in the ADA gene on chromosome 20q13.11
• Marked accumulations of adenosine, 2′-deoxyadenosine, and 2′-O-
methyladenosine lead directly or indirectly to T-cell apoptosis, which
causes the immunodeficiency.
• ADA-deficient patients usually have a much more profound lymphopenia
than do infants with other types of SCID, with mean absolute lymphocyte
counts of <500/mm3.
• The absolute numbers of T, B, and NK cells are very low.
• NK function is normal.

22. • Deficiency of ADA is an autosomal recessive genetic disorder.
• It accounts for about 10-15% of all cases of SCID.
• ADA deficiency may present in infancy, childhood, adolescence or
adulthood.
• Age of onset and severity is related to some 29 known genotypes
associated with the disorder.
• Accumulation of adenosine and deoxyadenosine follows and confers
a toxic effect on immature lymphocytes, particularly thymocytes,
which thus fail to mature.

23. • The deficiency causes a build up of toxic metabolites in all cells, but this
build up is specifically detrimental to developing T cells and B cells.
• Most of the body cells have effective means of removing these metabolic
by products and remain unaffected by ADA deficiency.
• However, T lymphocytes are unable to do so in the absence of ADA.
• Thus, T cells bear the brunt and affected individuals tend to have a small,
underdeveloped thymus.
• Consequently, the immune system is severely compromised or completely
lacking.
• Instead of having a normal life span of a few months, T cells of individuals
with ADA deficiency live only for a few days.

24. • After T-cell function is conferred by hematopoietic stem cell
transplantation without pretransplant chemotherapy, there is generally
excellent B-cell function despite the fact that the B cells are of host origin.
• This is because ADA deficiency affects primarily T-cell function.
• Milder forms of ADA deficiency have led to delayed diagnosis of
immunodeficiency, even to adulthood.
• Other distinguishing features of ADA-deficient SCID include the presence
of rib cage abnormalities similar to a rachitic rosary and numerous skeletal
abnormalities of chondr oosseous dysplasia, which occur predominantly at
the costochondral junctions, at the apophyses of the iliac bones, and in the
vertebral bodies where a “bone-in-bone” effect is observed.

25. • ADA deficiency is a rare type of immunodeficiency and its diagnosis is
critically dependent upon a high degree of suspicion and close
coordination between the clinician and immunological laboratory
services.
• Correct and early diagnosis assumes greater importance in this
disorder as the modern research has revolutionised the clinical
management of the condition, making it treatable, even curable in
many cases.

26. • As with other types of SCID, ADA deficiency can be cured by HLA identical
or haploidentical T-cell–depleted stem cell transplantation without the
need for pre- or posttransplant chemotherapy; this remains the treatment
of choice.
• Enzyme replacement therapy should not be initiated if stem cell
transplantation is possible because it confers graft-rejection capability.
• Enzyme replacement provides protective immunity but over time there is
a decline of lymphocyte counts and proliferative responses.
• A number of infants with ADA deficiency have become successfully
immune reconstituted by gene therapy.
• Spontaneous reversion to normal of a mutation in the ADA gene has also
been reported.

27. COMBINED IMMUNODEFICIENCY(CID)
• Combined immunodeficiency (CID) is distinguished from SCID by the
presence of low but not absent T-cell function.
• Similar to SCID, CID is a syndrome of diverse genetic causes.
• Patients with CID have recurrent or chronic pulmonary infections,
failure to thrive, oral or cutaneous candidiasis, chronic diarrhea,
recurrent skin infections, Gram-negative bacterial sepsis, urinary tract
infections, and severe varicella in infancy.
• Although they usually survive longer than infants with SCID, they fail
to thrive and die early in life.
• Neutropenia and eosinophilia are common.

28. • Serum immunoglobulins may be normal or elevated for all classes, but
selective IgA deficiency, marked elevation of IgE, and elevated IgD levels
occur in some cases.
• Although antibody-forming capacity is impaired in most patients, it is not
absent.
• Studies of cellular immune function show lymphopenia, profound
deficiencies of T cells, and extremely low but not absent lymphocyte
proliferative responses to mitogens, antigens, and allogeneic cells in vitro.
• Peripheral lymphoid tissues demonstrate paracortical lymphocyte
depletion.
• The thymus is very small, with a paucity of thymocytes and usually no
Hassall corpuscles.
• An autosomal recessive pattern of inheritance is common

29. PURINE NUCLEOSIDE PHOSPHORYLASE
DEFICIENCY
• Point mutations identified in the purine nucleoside phosphorylase
gene on chromosome 14q13.1 account for these deficiencies.
• In contrast to ADA deficiency, no characteristic physical or skeletal
abnormalities have been noted, but serum and urinary uric acid are
usually markedly deficient.
• Deaths result from generalized vaccinia, varicella, lymphosarcoma, or
GVHD mediated by allogeneic T cells in nonirradiated blood or bone
marrow.
• Two-thirds of patients have neurologic abnormalities, one-third of
patients have autoimmune diseases, and some have had allergic
diseases.

30. • Lymphopenia is striking, primarily because of a marked deficiency of
T cells.
• T-cell function is decreased to various degrees.
• B cell function may be near normal.
• The proportion of circulating NK cells is increased.
• Prenatal diagnosis or diagnosis at birth is possible.
• Bone marrow transplantation is the only successful form of therapy

31. CARTILAGE HAIR HYPOPLASIA
• Cartilage hair hypoplasia (CHH) is an unusual form of short-limbed
dwarfism with frequent and severe infections.
• Genetics and Pathogenesis CHH is an autosomal recessive condition.
Numerous mutations that cosegregate with the CHH phenotype have
been identified in the untranslated RNase MRP (RMRP) gene, which
has been mapped to chromosome 9p21-p13 .
• The RMRP endoribonuclease consists of an RNA molecule bound to
several proteins and has at least 2 functions: cleavage of RNA in
mitochondrial DNA synthesis and nucleolar cleaving of pre-RNA.
• Mutations in RMRP cause CHH by disrupting a function of RMRP RNA
that affects multiple organ systems

32. • In vitro studies show decreased numbers of T cells and defective T-
cell proliferation because of an intrinsic defect related to the G1
phase, resulting in a longer cell cycle for individual cells.
• NK cells are increased in number and function

33. Clinical Manifestations
• Clinical features include short, pudgy hands; redundant skin;
hyperextensible joints of hands and feet but an inability to extend the
elbows completely; and fine, sparse, light hair and eyebrows.
• Severe and often fatal varicella infections, progressive vaccinia, and
vaccine-associated poliomyelitis have been observed.
• Associated conditions include deficient erythrogenesis, Hirschsprung
disease, and an increased risk of malignancies.

34. • The bones radiographically show scalloping and sclerotic or cystic
changes in the metaphyses and flaring of the costochondral junctions
of the ribs.
• Three patterns of immune dysfunction have emerged: defective
antibody-mediated immunity, CID (most common), and SCID.
• Stem cell transplantation has resulted in immunologic reconstitution
in some CHH patients who had the SCID phenotype.

35. CASE NO.2
• A 15-month-old boy, born by spontaneous vaginal delivery of a non-
consanguineous marriage presented with second episode of bleeding
per rectum.
• There was no history of decreased urine output, no abdominal pain,
no swelling over body, no family history of similar illness in family.
• There was history suggestive of recurrent sinopulmonary and soft
tissue infections, eczematoid rashes which was started form scalp
and gradually progressed to all over body since early infancy which
was treated by many paediatricians.

36. • First episode of bleeding per rectum occurred 2 months back, during
first episode initially treated by a paediatrician as case of dysentery
but no improvement in the bleeding then he referred this case to
another hospital, where he was diagnosed as case of Hemolytic
Uremic syndrome.
• Patient was hospitalized for 40 days and managed with 6 times fresh
whole blood transfusion, broad spectrum antimicrobials and was
discharged on request when asymptomatic for 5 days.
• After 15 days of discharge patient again developed bleeding per
rectum and then brought to our institute

37. • Investigation during first episode revealed Hemoglobin 7.5 gm/dl,
TLC 12400/cmm, DLC-P58, L40, E02, Platelet count 20,000/cmm,
general blood picture (GBP) - microcytic hypochromic anemia, no
fragmented RBC, Tiny platelets, no immature cell, blood urea
18mg/dl, Creatinine 0.6 mg/dl, urine was normal normal on routine
examination and microscopy, inspite of 6 times fresh whole blood
transfusion predischarged platelet count was 36,000/cmm.

38. • On admission in our hospital he was afebrile, alert and active.
• He had mild pallor pulse rate 92 per minute, respiratory rate of 32 per
minute, weight 5.5 kg (less than 3rd centile), length 70 cm (less than 3rd
centile), sparse hair and eczematoid rash over the scalp, neck, skin folds of
upper and lower limbs.
• His head circumference was 43 cm (normal for age) and chest
circumference 41 cm.
• There were no congenital malformations.
• Respiratory, cardiovascular and central nervous system were within
normal limits while the liver was palpable 1 cm below the costal margin..

39. • Laboratory investigations revealed hemoglobin (Hb) of 9.6gm/dl, total
leukocyte count 11,800/cumm and platelet count 25,000/cumm. PT
(Prothrombin time) was 13 seconds and aPTT was 31 seconds
• P.S revealed normocytic hypochromic with microthrombocytopenia.
• Immunoglobulin profile showed high IgA, low IgM , High IgE and
normal IgG HIV serology was negative.

40. • Patients was managed with oral antimicrobials, multivitamins, one time@
20ml/kg fresh whole blood transfusions(because platelets concentrates not
available in our blood bank) and IV immunoglobulin at rate 400mg/kg, he
improved gradually, and pre discharged platelets count was 55,000/cumm.
• Parents were counselled regarding available treatments options and after
7 days of hospital stay he was dischared on Co-trimoxazole prophylaxis,
multivitamins & iron supplementation, emmoliants as advised by
dermatologist with advice of monthly IV Ig replacement therapy.
• He was on regular monthly Immunoglobulin replacement therapy in follow
up and doing well, and has gained weight 2 kg over past 5 months.

41. DIAGNOSIS ?
• WISKOTT ALDRICH SYNDROME
• Autoimmune lymphoproliferative syndrome
• IMMUNE-DYSREGULATION, POLYENDOCRINOPATHY, ENTEROPATHY, X-
LINKED SYNDROME
• Severe Combined Immunodeficiency (SCID)
• ADA DEFICIENCY
• ATAXIA-TELANGIECTASIA
• Autosomal Recessive Hyper-IgE Syndrome
• Autosomal Dominant Hyper-IgE Syndrome

42. Discussion
• The present case demonstrated characteristic clinical triad of Wiskott-
Aldrich syndrome-intermittent bleeding because of thrombocytopenia,
progressive eczema since early infancy and recurrent sinopulmonary
bacterial infections.
• Immunoglobulin profile showed high IgA, low IgM, High IgE and normal
IgG.
• Small platelets size and low platelets count clinched the diagnosis in favour
of Wiskott - Aldrich syndrome.
• At a later age when T cell functions are affected, opportunistic infections
may occur.
• Children who survive the first 8-10 years are at risk for the development of
lymphoid malignancies.

43. • The diagnosis of Wiscott Aldrich Syndrome is based on the
demonstration of increased serum IgA and IgE and decreased serum
IgM levels .
• Wiskott-Aldrich syndrome is a complex and severe X-linked disorder
characterized by microthrombocytopenia, eczema, immunodefi
ciency, and increased risk in developing autoimmunity and
lymphomas

44. IMMUNODEFICIENCY WITH THROMBOCYTOPENIA
AND ECZEMA (WISKOTT-ALDRICH SYNDROME)
• Wiskott-Aldrich syndrome, an X-linked recessive syndrome, is
characterized by atopic dermatitis, thrombocytopenic purpura with
normal-appearing megakaryocytes but small defective platelets, and
undue susceptibility to infection.
• Genetics and Pathogenesis- The abnormal gene, on the proximal
arm of the X chromosome at Xp11.22-11.23 near the centromere.
• It encodes a 501 amino acid proline rich cytoplasmic protein
restricted in its expression to hematopoietic cell lineages.

45. • The Wiskott-Aldrich syndrome protein (WASP) binds CDC42H2 and
rac, members of the Rho family of guanosine triphosphatases.
• Wiskott-Aldrich syndrome protein appears to control the assembly of
actin filaments required for microvesicle formation downstream of
protein kinase C and tyrosine kinase signaling.
• Carriers can be detected by demonstration of the deleterious
mutation

46. Clinical Manifestations
• Patients often have prolonged bleeding from the circumcision site or
bloody diarrhea during infancy.
• The thrombocytopenia is not initially due to antiplatelet antibodies.
• Atopic dermatitis and recurrent infections usually develop during the 1st
yr of life.
• Streptococcus pneumoniae and other bacteria having polysaccharide
capsules cause otitis media, pneumonia, meningitis, and sepsis.
• Later, infections with agents such as P. jiroveci and the herpesviruses
become more frequent.
• Survival beyond the teens is rare; infections, bleeding, and EBV-associated
malignancies are major causes of death.

47. • Anamnestic responses to protein antigens are poor or absent.
• There is an accelerated rate of synthesis as well as hypercatabolism of
albumin, IgG, IgA, and IgM, resulting in highly variable concentrations of
different immunoglobulins, even within the same patient.
• The predominant immunoglobulin pattern is a low serum level of IgM,
elevated IgA and IgE, and a normal or slightly low IgG concentration.
• Because of their profound antibody deficiencies, these patients should be
given monthly infusions of intravenous immunoglobulin (IVIG) regardless of
their serum levels of the different immunoglobulin isotypes.
• Percentages of T cells are moderately reduced, and lymphocyte responses
to mitogens are variably depressed.

48. Treatment
• Good supportive care includes appropriate nutrition, routine IVIG, use
of killed vaccines, aggressive management of eczema and associated
cutaneous infections, platelet transfusion for serious bleeding
episodes, splenectomy if a transplant is not going to be done.
• High-dose IVIG with systemic steroids for autoimmune complications.
• Bone marrow or cord blood transplantation is the treatment of choice
and is usually curative

49. CASE NO 3
• A 28-months-old Sudanese boy presented with delayed walking (20
month), unsteady gait and frequent falls, and delayed slurred speech.
• He had recurrent respiratory and ear infections associated with
psychomotor delay but his somatic growth was normal.
• On examination, he showed florid bulbar conjunctiva telengectasia
• Movement patterns demonstrated ataxia but no extra pyramidal
movements or ocular apraxia.

52. • Magnetic resonance image (MRI) showed cerebellar atrophy
• Investigations revealed low lymphocyte count and IgA.
• The child was treated symptomatically and supportively with
antibiotics for recurrent infections and multivitamins.
• Speech therapy was advised and intravenous immunoglobulin
therapy was suggested, but could not be afforded by the family

53. DIAGNOSIS ?
• WISKOTT ALDRICH SYNDROME
• Autoimmune lymphoproliferative syndrome
• IMMUNE-DYSREGULATION, POLYENDOCRINOPATHY, ENTEROPATHY, X-
LINKED SYNDROME
• Severe Combined Immunodeficiency (SCID)
• ADA DEFICIENCY
• ATAXIA-TELANGIECTASIA
• Autosomal Recessive Hyper-IgE Syndrome
• Autosomal Dominant Hyper-IgE Syndrome

54. ATAXIA-TELANGIECTASIA
• Ataxia-telangiectasia is a complex syndrome with immunologic,
neurologic, endocrinological, hepatic, and cutaneous abnormalities.
• Genetics and Pathogenesis-The mutated gene responsible for this
defect, ataxia-telangiectasia mutation (ATM), was mapped to the long
arm of chromosome 11 (11q22-23) and has been cloned.
• The gene product is a DNA-dependent protein kinase localized
predominantly to the nucleus and involved in mitogenic signal
transduction, meiotic recombination, and cell-cycle.

55. • Cells from patients, as well as from heterozygous carriers, have
increased sensitivity to ionizing radiation, defective DNA repair, and
frequent chromosomal abnormalities.
• In vitro tests of lymphocyte function have generally shown
moderately depressed proliferative responses to T- and B-cell
mitogens.
• Percentages of CD3 and CD4 T cells are moderately reduced.
• The thymus is very hypoplastic, exhibits poor organization, and lacks
Hassall corpuscles.

56. Clinical Manifestations
• The most prominent clinical features are progressive cerebellar ataxia,
oculocutaneous telangiectasias, chronic sinopulmonary disease, a
high incidence of malignancy, and variable humoral and cellular
immunodeficiency.
• Ataxia typically becomes evident soon after these children begin to
walk and progresses until they are confined to a wheelchair, usually
by the age of 10-12 yr.
• The telangiectasias begin to develop at 3-6 yr of age.
• The most frequent humoral immunologic abnormality is the selective
absence of IgA, which occurs in 50-80% of these patients

57. • Hypercatabolism of IgA also occurs.
• IgE concentrations are usually low, and the IgM may be of the low-
molecular-weight variety.
• IgG2 or total IgG levels may be decreased, and specific antibody titers
may be decreased or normal.
• Recurrent sinopulmonary infections occur in approximately 80% of
these patients.
• The malignancies associated with ataxia-telangiectasia are usually of
the lymphoreticular type, but adenocarcinomas also occur.
• Unaffected relatives have an increased incidence of malignancy.

58. HYPER-IGE SYNDROMES
• The hyper-IgE syndromes are relatively rare primary immunodeficiency
syndromes characterized by recurrent severe staphylococcal abscesses of
the skin, lungs, and other sites and markedly elevated levels of serum IgE .
• They occur in 2 forms: autosomal dominant and autosomal recessive.
• Autosomal Dominant Hyper-IgE Syndrome-also known as the Buckley
syndrome.
• Genetics and Pathogenesis- The autosomal dominant hyper-IgE syndrome
is caused by heterozygous mutations in the gene encoding STAT-3.
• These mutations result in a dominant negative effect on the expression of
STAT-3 by the other nonmutated gene.
• It is not clear exactly how the STAT-3 mutation causes all parts of the
syndrome, but it is thought that IL-17 deficiency may account in part for
the susceptibility to Candida infection.

59. • IL-17 is a cytokine that acts on monocytes to induce secretion of
proinflammatory mediators such as IL-8, TNF, and granulocyte-
macrophage colony-stimulating factor.
• Clinical Manifestations-The characteristic clinical features of the
autosomal dominant form of the hyper-IgE syndrome are
staphylococcal abscesses, pneumatoceles, osteopenia, and unusual
facial features.
• There is a history from infancy of recurrent staphylococcal abscesses
involving the skin, lungs, joints, viscera and other sites.
• Persistent pneumatoceles develop as a result of recurrent pneumonia

60. • They often have histories of sinusitis and mastoiditis.
• C.albicans is the second most common pathogen.
• Allergic respiratory symptoms are usually absent.
• The pruritic dermatitis that occurs is not typical atopic eczema and
does not always persist.
• The first 2 reported patients were described as having coarse facial
features, including a prominent forehead, deep-set wide-spaced eyes,
a broad nasal bridge, a wide fleshy nasal tip, mild prognathism, facial
asymmetry, and hemihypertrophy.

61. • In older children, delay in shedding primary teeth, recurrent
fractures, and scoliosis occur.
• These patients demonstrate an exceptionally high serum IgE
concentration; an elevated serum IgD concentration.
• Usually normal concentrations of IgG, IgA, and IgM
• Pronounced blood and sputum eosinophilia; abnormally low
anamnestic antibody responses; and poor antibody and cell-mediated
responses to neoantigens.

62. • Traditionally, IgE levels >2000 IU/mL confirm the diagnosis.
• However, IgE levels may fluctuate and even decrease in adults.
• In neonates and infants with the pruritic pustular dermatosis, IgE levels
will be elevated for age and are usually in the 100s.
• Most patients have normal T-lymphocyte proliferative responses to
mitogens but very low or absent responses to antigens or allogeneic cells
from family members

63. • Blood, sputum, and histologic sections of lymph nodes, spleen, and
lung cysts show striking eosinophilia.
• Hassall corpuscles and thymic architecture are normal.
• Phagocytic cell ingestion, metabolism, killing, and total hemolytic
complement activity are normal in all patients, and results of
chemotaxis studies have been mostly normal.

64. Autosomal Recessive Hyper-IgE Syndrome
• Genetics and Pathogenesis-With the exception of 1 patient who had
a mutation in the gene encoding Tyk2, most reported patients with
autosomal recessive hyper-IgE syndrome have had mutations in the
gene encoding DOCK8, which is on chromosome 9.
• DOCK8 is a member of the 11-member DOCK protein family. DOCK8 is
likely to function as a guanine exchange factor for the Rho-guanosine
triphosphatases Cdc42 and Rac1.
• Guanosine triphosphatase activation induces dynamic filamentous
actin rearrangements and lamellipodia formation, leading to cell
growth, migration, and adhesion.

65. • DOCK8 may be important for the formation of the immunologic
synapse that leads to T-cell activation, proliferation, and
differentiation.
• It may rarely be due to mutations in phosphoglucomutase 3 (PGM3
deficiency).
• ClinicalManifestations -Unlike those with the autosomal dominant
form of this syndrome, a large majority of patients with autosomal
recessive hyper-IgE have severe atopic dermatitis, asthma, food
allergies, and anaphylaxis.

66. • They also have recurrent skin viral infections, including severe herpes
simplex, herpes zoster, molluscum contagiosum, and papillomavirus
skin infections.
• Malignancies are also more common than in the autosomal dominant
form.
• Patients with the autosomal recessive hyper-IgE syndrome do not
have pneumatoceles, a history of fractures, unusual facial features, or
delayed shedding of the baby teeth, as seen with the autosomal
dominant form of the hyper-IgE syndrome.

67. • Most patients with autosomal recessive hyper-IgE have elevated
serum IgE levels, low serum IgM levels, and variable IgG antibody
responses.
• They also have eosinophilia and lymphopenia, low T-cell numbers and
impaired T-cell function.
• Their immunologic phenotype is that of a CID.

68. Treatment
• The most effective therapy for the autosomal dominant hyper-IgE
syndrome is long-term administration of therapeutic doses of a
penicillinase-resistant antistaphylococcal antibiotic, adding other
agents as required for specific infections.
• IVIG should be administered to antibody-deficient patients, and
appropriate thoracic surgery should be provided for superinfected
pneumatoceles or those persisting beyond 6 months.

69. • Bone marrow transplantation has been variably successful in this
condition.
• The prognosis in the autosomal recessive form of the hyper-IgE
syndrome is much poorer than in the autosomal dominant form, and
most patients die early .
• The treatment of choice for the autosomal recessive form is
allogeneic bone marrow transplantation

71. Treatment of Cellular or Combined
Immunodeficiency
• Good supportive care, including prevention and treatment of infections, is
critical while patients await more definitive therapy
• Having knowledge of the pathogens causing disease with specific immune
defects is also useful
• Transplantation of MHC-compatible sibling or rigorously T-cell– depleted
haploidentical (half-matched) parental hematopoietic stem cells is the
treatment of choice for patients with fatal T-cell or combined T- and B-cell
defects.
• The major risk to the recipient from transplants of bone marrow or
peripheral blood stem cells is GVHD from donor T cells.
.

72. • Patients with less severe forms of cellular immunodeficiency,
including some forms of CID, Wiskott-Aldrich syndrome, cytokine
deficiency, and MHC antigen deficiency, reject even HLA identical
marrow grafts unless chemoablative treatment is given before
transplantation

73. • Several patients with these conditions have been treated successfully
with hematopoietic stem cell transplantation after conditioning.
• More than 90% of patients with primary immunodeficiency
transplanted with HLA-identical related marrow will survive with
immune reconstitution.
• T-cell–depleted haploidentical-related marrow transplants in patients
with primary immunodeficiency have had their greatest success in
patients with SCID, who do not require

74. • By contrast, in ADA-deficient SCID, there has been outstanding
success without insertional oncogenesis.
• More recently, gene therapy has been successful in the Wiskott-
Aldrich syndrome but unfortunately with the problem of insertional
mutagenesis.

76. Immune Dysregulation with Autoimmunity
(or) Lymphoproliferation
• AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME(ALPS)-Autoimmune
lymphoproliferative syndrome (ALPS), also known as Canale-Smith
syndrome, is a disorder of abnormal lymphocyte apoptosis leading to
polyclonal populations of T cells (double-negative T cells), which express
CD3 and α/β antigen receptors but do not have CD4 or CD8 coreceptors
(CD3 + T cell receptor α/β+ CD4− CD8−).
• These T cells respond poorly to antigens or mitogens and do not produce
growth or survival factors (IL-2).
• The genetic deficit in most patients is a germline or somatic mutation in
the Fas gene, which produces a cell-surface receptor of the TNF receptor
superfamily (TNFRSF6), which, when stimulated by its ligand, will produce
programmed cell death

77. • Persistent survival of these lymphocytes leads to immune
dysregulation and autoimmunity.
• ALPS is also caused by other genes in the Fas pathway (FASLG and
CASP10) .
• In addition, ALPS-like disorders are associated with other mutations;
RAS-associated autoimmune lymphoproliferative disorder (RALD),
CASPASE-8 deficiency syndrome (CEDS), Fas-associated protein with
death domain deficiency (FADD), and protein kinase C delta deficiency
(PRKCD).

78. • These disorders have varying degrees of immune deficiency,
autoimmunity and lymphoproliferation.
• Clinical Manifestations-ALPS is characterized by autoimmunity,
chronic persistent or recurrent lymphadenopathy, splenomegaly,
hepatomegaly (in 50%), and hypergammaglobulinemia (IgG, IgA).
• Many patients present in the 1st yr of life, and most are symptomatic
by yr 5.
• Lymphadenopathy can be striking .
• Splenomegaly may produce hypersplenism with cytopenias.

79. • Autoimmunity also produces anemia or thrombocytopenia or a mild
neutropenia.
• The lymphoproliferative process (lymphadenopathy, splenomegaly)
may regress over time, but autoimmunity does not and is
characterized by frequent exacerbations and recurrences.
• Other autoimmune features include urticaria, uveitis,
glomerulonephritis, hepatitis, vasculitis, glomerulonephritis,
vasculitis, panniculitis, arthritis, and central nervous system
involvement (seizures, headaches, encephalopathy).

80. • Malignancies are also more common in patients with ALPS and include
Hodgkin and non-Hodgkin lymphomas and solid-tissue tumors of thyroid,
skin, heart, or lung.
• ALPS is one cause of Evan syndrome (immune thrombocytopenia and
immune hemolytic anemia).
• Diagnosis Laboratory abnormalities depend on the lymphoproliferative
organ response (hypersplenism) or the degree of autoimmunity (anemia,
thrombocytopenia).
• There may be lymphocytosis or lymphopenia.
• Flow cytometry helps identify the lymphocyte type .
• Functional genetic analysis for the TNFRSF6 gene often reveals a
heterozygous mutation

82. Treatment
• Lymphoproliferative manifestations have been managed with
corticosteroids and immunosuppressive agents (Cytoxan
[cyclophosphamide], methotrexate, azathioprine); once weaned, the
manifestation recurs.
• Hypersplenism may require splenectomy.
• Malignancies can be treated with the usual protocols used in patients
unaffected by ALPS.
• Stem cell transplantation is another possible option in treating the
autoimmune manifestations of ALPS.

83. IMMUNE-DYSREGULATION,
POLYENDOCRINOPATHY, ENTEROPATHY, X-LINKED
SYNDROME
• This immune dysregulation syndrome is characterized by onset within the
1st few wk or mo of life with watery diarrhea (autoimmune enteropathy),
an eczematous rash (erythroderma in neonates), insulin-dependent
diabetes mellitus, hyperthyroidism or more often hypo thyroidism, severe
allergies, and other autoimmune disorders (Coombs-positive hemolytic
anemia, thrombocytopenia, neutropenia).
• Psoriasiform or ichthyosiform rashes and alopecia have also been
reported, Immune-dysregulation, polyendocrinopathy, enteropathy, X-
linked (IPEX) syndrome is caused by a mutation in the FOXP3 gene, which
encodes a forkhead-winged helix transcription factor (scurfin) involved in
the function and development of CD4+CD25+ regulatory T cells.

84. • The absence of regulatory cells may predispose to abnormal
activation of effector T cells.
• Dominant gain of function mutations in STAT1 and other gene
mutations produces an IPEX-like syndrome.
• Clinical Manifestations-Watery diarrhea with intestinal villous
atrophy leads to failure to thrive in most patients.
• Cutaneous lesions (usually eczema) and insulin-dependent diabetes
begin in infancy.
• Lymphadenopathy and splenomegaly are also present

85. • . Serious bacterial infections (meningitis, sepsis, pneumonia,
osteomyelitis) may be related to neutropenia, malnutrition, or
immune dysregulation.
• Laboratory features reflect the associated autoimmune diseases,
dehydration, and malnutrition.
• In addition, serum IgE levels are elevated with normal levels of IgM,
IgG, and IgA.

86. • The diagnosis is made clinically and by mutational analysis of the FOXP3
gene.
• Treatment-Inhibition of T-cell activation by cyclosporine, tacrolimus, or
sirolimus with steroids is the treatment of choice, along with the specific
care of the endocrinopathy and other manifestations of autoimmunity.
• Stem cell transplantation is the only possibility for curing IPEX.
• Overall, the combination of the risks for serious bacterial infection in the
untreated condition and the risks of immunosuppression and bone marrow
transplantation gives IPEX a poor prognosis.
• Untreated, most die by 2 yr of age.

87. • THANK YOU