The document discusses primary immunodeficiencies (PIDs), which are genetic disorders caused by defects in the immune system. It describes several key properties of the immune system and outlines deficiencies that can occur in both the innate and adaptive immune systems. Specific PIDs are then discussed in detail, including symptoms, diagnosis, and treatment options. The document emphasizes the importance of early diagnosis and molecular testing to determine the most appropriate treatment for each PID.
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
6.
7.
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10.
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
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
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
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
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)
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
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
48.
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
Editor's Notes
highly diverse repertoire of antigen receptors that enables recognition of a nearly infinite range of pathogens;
immune memory, to mount rapid recall immune responses;
immunologic tolerance, to avoid immune damage to normal self-tissues.
Immunity is intrinsic to life and an important tool in the fight for survival against pathogenic microorganisms
Innate- Cells of the innate immune system include natural killer cell lymphocytes, monocytes/macrophages, dendritic cells, neutrophils, basophils, eosinophils, tissue mast cells, and epithelial cells
Adaptive- these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during development and throughout the life of the organism
locations of the sites of infection and the causal microorganisms involved help arrive at a proper diagnoses
can also lead to immunopathologic responses such as allergy and autoimmunity
Hematopoietic stem cells (HSCs) differentiate into common myeloid progenitors (CMPs) and then granulocyte-monocyte progenitors (GM-prog.), which, in turn, differentiate into neutrophils (MB: myeloblasts; Promyelo: promyelocytes; myelo: myelocytes) or monocytes (monoblasts and promonocytes). Upon activation, neutrophils adhere to the vascular endothelium, transmigrate, and phagocytose the targets. Reactive oxygen species (ROS) are delivered to the microorganism-containing phagosomes. Macrophages in tissues kill using the same mechanism. Following activation by interferon (not shown here), macrophages can be armed to kill intracellular pathogens such as mycobacteria. For sake of simplicity, not all cell differentiation stages are shown. The abbreviations for PIDs are contained in boxes placed at corresponding stages of the pathway. SCN, severe congenital neutropenia; WHIM, warts, hypogammaglobulinemia, immunodeficiency myelokathexis; LAD, leukocyte adhesion deficiencies; CGD, chronic granulomatous diseases; MSMD, Mendelian susceptibility to mycobacterial disease.
can develop bleeding because the 2 integrin in platelets is not functional
70% of cases are associated with X-linked recessive inheritance versus autosomal inheritance in the remaining 30%.
causes deep-tissue bacterial and fungal abscesses in macrophage-rich organs such as the lymph nodes, liver, and lungs
Macrophage-rich granulomas can often arise in the liver, spleen, and other organs. These are sterile granulomas that cause disease by obstruction (bladder, pylorus, etc.) or inflammation (colitis, restrictive lung disease).
recessive mutations in genes that encode essential adaptor molecules involved in the signaling pathways of the majority of known Toll-like receptors
Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which, in turn, give rise to the T cell precursors that migrate to the thymus. The development of CD4+ and CD8+ T cells is shown. Known T cell effector pathways are indicated, i.e., cells, cytotoxic T cells (Tc), TH1, TH2, TH17, TFh (follicular helper) CD4 effector T cells, regulatory T cells (Treg), and natural killer T cells (NKTs); abbreviations for PIDs are contained in boxes. Vertical bars indicate a complete deficiency; broken bars a partial deficiency. SCID, severe combined immunodeficiency; ZAP 70, zeta-associated protein deficiency, MHCII, major histocompatibility complex class II deficiency; TAP, TAP1 and 2 deficiencies; Orai1, Stim1 deficiencies; HLH, hematopoietic lymphohistiocytosis; MSMD, Mendelian susceptibility to mycobacterial disease; Tyk2, DOCK8, autosomal recessive form of hyper-IgE syndrome; STAT3, autosomal dominant form of hyper-IgE syndrome; CD40L, ICOS, SAP deficiencies; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; XLP, X-linked proliferative syndromes.
Lymphocytopenia is strongly suggestive of SCID in more than 90% of cases
induce premature cell death of lymphocyte progenitors -- results in the absence of B, NK lymphocytes and T cells
result from mutations in genes encoding proteins that mediate the recombination of V(D)J gene elements in T and B cell antigen receptor genes.
extremely rare
consequence of hypomorphic mutations in genes usually associated with SCID or Artemis or IL-7R
patients are very fragile, requiring simultaneous anti-infective therapy, nutritional support, and immunosuppression.
b. caused by a mutation in the calcium channel gene (ORAI-) or its activator (STIM-1)
AT should be considered in young children with IgA deficiency
caused by a mutation in the gene encoding the ATM protein
With high risk of lymphoma, leukemia and carcinomas
It is caused by the mutation of genes encoding telomere maintenance proteins, including dyskerin (DKC1)
cytogenetic analysis of multiradial aspects in multiple chromosomes (most frequently 1, 9, and 16)
Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which give rise to pre-B cells. The B cell differentiation pathway goes through the pre–B cell stage (expression of the heavy chain and surrogate light chain), the immature B cell stage (expression of surface IgM), and the mature B cell stage (expression of surface IgM and IgD). The main phenotypic characteristics of these cells are indicated. In lymphoid organs, B cells can differentiate into plasma cells and produce IgM or undergo (in germinal centers) Ig class switch recombination (CSR) and somatic mutation of the variable region of V genes (SHM) that enable selection of high-affinity antibodies. These B cells produce antibodies of various isotypes and generate memory B cells. PIDs are indicated in the purple boxes. CVID: common variable immunodeficiency.
Determination of antibody production following immunization (tetanus toxoid vaccine or nonconjugated pneumococcal polysaccharide antigens)
Predispose to severe, chronic, disseminated enteroviral infections causing meningoencephalitis, hepatitis, and dermatomyositis-like disease
mutations in the autoimmune regulator (AIRE) gene results in impaired thymic expression of self-antigens