2.  Immune System
- defense mechanisms to protect the host from microbes
and their virulence factors]
• 3 Key Properties:
1. highly diverse antigen receptors
2. immune memory
3. immunologic tolerance

3. 1. Innate Immune System
- rapid triggering of inflammatory responses
- all cell lineages
2. Adaptive Immune System
- mediated by T and B lymphocytes
- antigen-presenting cells

4. - expression or function of gene products is genetically
impaired
- Mendelian inheritance
- overall prevalence of PIDs ~ 5 per 100,000 individuals
- combination of recurrent infections, inflammation and
autoimmunity

5. - presence of recurrent or unusually severe infections
- detailed personal and family medical history
 genetic tests – Definitive Diagnosis

11. Deficiency of the Innate System
1. Severe Congenital Neutropenia
 impaired neutrophil counts (<500 /L of blood)
 absence of pus
 premature cell death of granulocyte precursors
 Diaqnosis:
- bone marrow (block in granulopoiesis at the
promyelocytic stage

12.  Treatment:
- hygiene
- trimethoprim/sulfamethoxazole
- SQ injection (G-CSF

13. 2. Asplenia
 infections by encapsulated bacteria
 Diagnosis:
- abdominal UTZ
- Howell-Jolly bodies

14.  Treatment:
- oral penicillin
- vaccination

15. 3. Leukocyte Adhesion Deficiency (LAD)
a. LAD I
- Most common
- caused by mutations in the 2 integrin gene

16. b. LAD II
- extremely rare
- defect in selectin-mediated leukocyte
c. LAD III
- defect in a regulatory protein
- can develop bleeding
- causes impaired wound healing and delayed loss of the
umbilical cord

17. • pus-free skin/tissue infections and massive
hyperleukocytosis (>30,000/L)
• Diagnosis:
- Immunofluorescence
 Treatment:
- Hematopoietic Stem Cell Transplantation (HSCT)

18. 4. Chronic Granulomatous Diseases
- impaired phagocytic killing of microorganisms by
neutrophils and macrophages
- incidence is approximately 1 per 200,000 live births
- causes deep-tissue bacterial and fungal abscesses in
macrophage-rich organs

19. Infectious Agents:
-Staphylococcus aureus and Serratia marcescens
-Burkholderia cepacia
- Fungi (Aspergillus)

20. - defective production of reactive oxygen species in the
phagolysosome membrane
- results from the lack of a component of NADPH oxidase
 Treatment:
- trimethoprim/sulfamethoxazole
- Daily administration of azole derivatives (intraconazole)
- HSCT

21. 5. Mendelian Susceptibility to Mycobacterial Disease
- defect in the IL-12 interferon (IFN) leading to impaired
IFN--dependent macrophage activation
- Tuberculous & nontuberculous mycobacteria -- Hallmark
- prone to developing Salmonella infections
- Treatment: interferon

22. 6. Toll-Like Receptor (TLR) Pathway Deficiencies
- specific susceptibility to herpes simplex encephalitis
- Susceptibility to both invasive, pyogenic infections and
mycobacteria

23. 7. Complement Deficiency
- composed of plasma proteins that leads to the deposition
of C3b fragments
- deficiency in classic pathway (C1q, C1r, C1s, C4, and
C2) can predispose an individual to bacterial

24.  Diagnosis:
- functional assays (CH50 and AP50 tests)
 Treatment:
- daily administration of oral penicillin

25. PRIMARY IMMUNODEFICIENCIES OF THE
ADAPTIVE IMMUNE SYSTEM
(T Lymphocyte Deficiencies)

26. 1. SEVERE COMBINED IMMUNODEFICIENCIES
- complete absence of these cells (block in T cell development)
- estimated to be 1 in 50,000 to 100,000 live births
 Clinical Manifestations:
- recurrent oral candidiasis
- failure to thrive
- protracted diarrhea
- acute interstitial pneumonitis caused by Pneumocystis jiroveci

27.  Diagnosis:
- Lymphocytopenia
- - absence of a thymic shadow on a chest x-ray
- determination of the number of circulating T, B, and NK
lymphocytes– (Accurate Diagnosis)

28. • Mechanisms:
a. Cytokine-Signaling Deficiency
- most frequent SCID phenotype
- absence of both T and NK cells

29. b. Purine Metabolism Deficiency
- deficiency in adenosine deaminase (ADA)
- induce premature cell death of lymphocyte progenitors
- cause bone dysplasia with abnormal costochondral
junctions and metaphyses and neurologic defects

30. c. Defective Rearrangements of T and B Cell Receptors
- selective deficiency in T and B lymphocytes
- account for 20-30% of SCID
- Can cause developmental defects

31. d. Defective (Pre-)T Cell Receptor Signaling in the
Thymus
- deficiencies in CD3 subunits associated with the
(pre)TCR and CD45
e. Reticular Dysgenesis
- causes T and NK deficiencies with severe neutropenia
and sensorineural deafness
- results from an adenylate kinase 2 deficiency

32. f. Defective Egress of Lymphocytes
- very low T cell counts
- result from a deficiency in coronin-1A
 Treatment:
- anti-infective therapies
- immunoglobulin replacement
- parenteral nutrition support
- HSCT
- a pegylated enzyme

33.  THYMIC DEFECTS
- profound T cell defect
a. DiGeorge syndrome
-constellation of developmental defects
-thymus is completely absent
 Diagnosis
- Immunofluorescence (hemizygous deletion in the long
arm of chromosome 22)

34. b. CHARGE
-coloboma of the eye, heart anomaly, choanal atresia,
retardation, genital and ear anomalies syndrome
 Treatment: thymic graft

35.  OMENN SYNDROME
- erythrodermia, alopecia, hepatosplenomegaly and
failure to thrive
- T cell lymphocytosis, eosinophilia, and low B cell count
 Treatment: HSCT

36.  FUNCTIONAL T CELL DEFECTS
- partially preserved T cell differentiation
- Causes chronic diarrhea and failure to thrive
- Diagnosis:
- Phenotyping
- in vitro functional assays

37. a. Zeta-Associated Protein 70 (ZAP70) Deficiency
- complete absence of CD8+ T cells
b. Calcium Signaling Defects
- defective antigen receptor-mediated Ca2+ influx
- prone to autoimmune manifestations (blood cytopenias)
and nonprogressive muscle disease

38. c. Human Leukocyteantigen (HLA) Class II Deficiency
- low but variable CD4+ T cell counts
- defective antigen-specific T and B cell responses
- susceptible to herpesvirus, adenovirus and enterovirus
infections and chronic gut/liver Cryptosporidium
infections

39. d. HLA Class I Deficiency
- reduced CD8+ T cell counts
- loss of HLA class I antigen expression
- cause chronic obstructive pulmonary disease and severe
vasculitis

40. a. Ataxia-Telangiectasia (AT)
- autosomal recessive disorder
- causes B cell defects
- progressive T cell immunodeficiency
- hallmark features: telangiectasia and cerebellar ataxia
- young children with IgA deficiency

41.  Diagnosis:
- cytogenetic analysis (chromosomes 7 and 14)
 Treatment: immunoglobulin replacement

42. b. Nijmegen Breakage Syndrome (NBS)
- severe T and B cell combined immune deficiency with
autosomal recessive inheritance
- exhibit microcephaly and a bird-like face
- risk of malignancies is very high
- deficiency in Nibrin caused by hypomorphic mutations

43. c. Dyskeratosis Congenita (Hoyeraal-Hreidarsson
Syndrome)
- absence of B and NK lymphocytes
- progressive bone marrow failure, microcephaly, in utero
growth retardation and gastrointestinal disease

44. d. Immunodeficiency with Centromeric and Facial
Anomalies (ICF)
- mild T cell immune deficiency with a more severe B cell
immune deficiency
- Features: coarse face, digestive disease, and mild
mental retardation
 Diagnostic:
- cytogenetic analysis

45. - elevated serum IgE levels
 Autosomal Recessive Hyper-IgE Syndrome
- T and B lymphocyte counts are low
- recurrent bacterial infections in the skin and respiratory
tract
- pox viruses and human papillomaviruses

46. - mutation in the gene encoding the transcription factor
STAT3
- combination of recurrent skin and lung infections
complicated by pneumatoceles
- caused by pyogenic bacteria and fungi
 Features:
- facial dysmorphy, defective loss of primary teeth,
hyperextensibility, scoliosis, and osteoporosis
- Elevated serum IgE levels

47. - caused by mutations in the RMRP gene for a noncoding
ribosome-associated RNA
- short-limb dwarfism, metaphyseal dysostosis and sparse
hair
- can predispose to erythroblastopenia, autoimmunity,
and tumors

49. - B cell immune deficiency
- leads to profound deficiency (IgG, IgA, and IgE)
- prone to opportunistic infections (interstitial
pneumonitis), cholangitis (Cryptosporidium) and
infection of the brain (Toxoplasma gondii)

50. - incidence of approximately 1 in 200,000 live births
- caused by mutations in the WASP gene
- relative CD8+ T cell deficiency with low serum IgM
levels and decreased antigen-specific antibody
responses
- clinical manifestations: recurrent bacterial infections,
eczema, and bleeding

51. - Complications: bronchopulmonary infections, viral
infections, severe eczema, autoimmune manifestations,
lymphoma
- Thrombocytopenia can be severe
- typical feature: reduced-sized platelets on a blood
smear

52.  Diagnosis: intracellular immunofluorescence analysis of
WAS protein
 Treatment:
- Prophylactic antibiotics, immunoglobulin G (IgG)
supplementation, topical treatment of eczema
- splenectomy improves platelet count
- Allogeneic HSCT is curative

53. - account for 60-70% of all cases
- B lymphocytes antibodies: IgM, IgG, IgA
 Defective antibody production results to:
- invasive, pyogenic bacterial infections
- recurrent sinus and pulmonary infections (Streptococcus
pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis)

54. - Parasitic infections (Giardia lambliasis) bacterial
infections (Helicobacter and Campylobacter) of the gut
- infections rarely occur before the age of 6 months
 Diagnosis:
- determination of serum Ig levels
- Determination of antibody production
- B cell phenotype determination in switched and
nonswitched memory B cells

55. - complete lack of antibody production
- mutation in the BTK gene
- severe, chronic, disseminated enteroviral infections
- Diagnosis: examination of bone marrow B cell precursors
- Treatment: immunoglobulin replacement

56. - characterized by defective Ig CSR
- results in very low serum levels of IgG and IgA and
elevated or normal serum IgM levels
- have enlarged lymphoid organs
- result from fetal rubella syndrome
 Diagnosis:
- screening for an X-linked CD40L deficiency and an
autosomal recessive CD40 deficiency

57. - characterized by low serum levels of one or more Ig
isotypes
- prevalence is estimated to be 1 in 20,000
- develop lymphoproliferation (splenomegaly),
granulomatous lesions, colitis, antibody-mediated
autoimmune disease, and lymphomas

58.  Diagnosis:
- should exclude the presence of hypomorphic mutations
associated with agammaglobulinemia or more subtle T cell
defects

59. - IgA deficiency -- most common
- increased numbers of acute and chronic respiratory
infections (bronchiectasis)
- increased susceptibility to drug allergies, atopic
disorders, and autoimmune diseases
- IgA deficiency may progress to CVID
 Treatment: immunoglobulin replacement

60. - prone to S. pneumoniae and H. influenzae infections of
the respiratory tract
- Defective production of antibodies against
polysaccharide antigens
- a defect in marginal zone B cells, a B cell subpopulation
involved in T-independent antibody responses

61. -IgG antibodies have a half-life of 21-28 days
 Treatment:
- injection of plasma-derived polyclonal IgG (repeated every 3-4
weeks, with a residual target level of 800 mg/mL in patients
who had very low IgG level)
- Immunoglobulin replacement can be performed by IV or
subcutaneous routes (800 mg/mL once a week)--lifelong
therapy
 main goal is to reduce the frequency of the respiratory tract
infections and prevent chronic lung and sinus disease

62. a. Hemophagocytic Lymphohistiocytosis
- unremitting activation of CD8+ T lymphocytes and
macrophages that leads to organ damage (liver, bone
marrow, and CNS)
- results from impair T and NK lymphocyte cytotoxicity
- EBV is the most frequent trigger

63.  Clinical Features:
- fever, hepatosplenomegay, edema, neurologic diseases,
blood cytopenia, increased liver enzymes,
hypofibrinogenemia, high triglyceride levels, elevated
markers of T cell activation

64.  Diagnosis:
- Functional assays of postactivation cytotoxic granule
exocytosis
 The conditions can be classified into three subsets:
1. Familial HLH with autosomal recessive inheritance,
including perforin deficiency

65. 2. HLH with partial albinism
- hair examination can help in the diagnosis
- Chediak-Higashi syndrome, Griscelli syndrome, and
Hermansky Pudlak syndrome type II

66. 3. X-linked proliferative syndrome (XLP)
- induction of HLH following EBV infection
- May develop progressive hypogammaglobulinemia
- life-threatening complication
 Treatment:
-immunosuppression (cytotoxic agent VP-16 or anti-T cell
antibodies)
- HSCT

67. - nonmalignant T and B lymphoproliferation
- caused by a defect in Fas-mediated apoptosis of
lymphocytes
- causing splenomegaly and enlarged lymph nodes
- Hallmark: CD4 -CD8- TCR+ T cells (20-50%)

68. - 70% of patients also display autoimmune manifestations
(autoimmune cytopenias, Guillain-Barre syndrome,
uveitis, and hepatitis)
 Treatment: pro-apoptotic drugs

69. - Several PIDs can cause severe gut inflammation
a. Immunodysregulation Polyendocrinopathy Enteropathy
X-linked Syndrome (IPEX)
- caused by loss-of-function mutations in the gene
encoding the transcription factor FOXP3
- widespread inflammatory enteropathy, food
intolerance, skin rashes, autoimmune cytopenias and
diabetes
 Treatment: allogeneic HSCT

70. b. Autoimmune Polyendocrinopathy Candidiasis
Ectodermal Dysplasia (APECED) Syndrome
- mutations in the autoimmune regulator (AIRE) gene
- Candida infection is often associated with this syndrome

71.  important to raise awareness of these diseases
 early diagnosis is essential for establishing an
appropriate therapeutic regimen
 A precise molecular diagnosis is not only necessary for
initiating the most suitable treatment but it is also
important for genetic counseling and prenatal diagnosis