TEXTBOOK OF IMMUNOLOGY - Mercury Podillya 2013

CONGENITAL IMMUNE DEFICIENCY

Phagocytic System Deficiency

Frequency: 10-12% of the total number of Primary immunodeficiencies (Tables 51, 56, 57, 58, 59, 60, 61, 62).

Class="center">Chédiak-Steinbrinck-Higashi Syndrome

Specific defect. Loss of the ability of neutrophils to release lysosomal Enzymes while maintaining the capacity for phagosome-lysosome fusion. Chemotaxis impairment.

Clinical Features. Characterized by albinism, Skin photosensitivity, and severe recurrent pyogenic infections caused primarily by streptococci and staphylococci. In such patients, neutrophils contain giant Lysosomes that retain The ability to fuse with phagosomes but fail to release their internal enzymes. As a result, the microbicidal capacity against microorganisms is impaired.

Immunological evaluation reveals impaired neutrophil chemotaxis and phagocytosis against the Background of normal B- and T-Cell function, as well as normal Complement levels. A deficiency of natural killer Cells is observed. The chemotaxis impairment is associated with disrupted Stability of the cytoskeletal microtubules (Tables 51, 56).

Treatment is symptomatic, utilizing appropriate Antibiotics. The prognosis is unfavorable. Typically, death occurs no later than 7 years of age due to early-onset malignancies or severe bacterial infections. The inheritance pattern is autosomal recessive.

Table 56. Combined T- and B-Cell Immunodeficiencies

Disease		Circulating T cells		Circulating B cells	Serum Ig	Associated features		Inheritance	Genetic defect / predominant Pathogenesis
1. T-B+ SCID*
γc deficiency		Markedly decreased		Normal or increased	Decreased	Markedly decreased NK cells		XL	Defect in the γ-chain of IL-2, 4, 7, 9, 15, 21 receptors
JAK3 deficiency		Markedly decreased		Normal or increased	Decreased	Markedly decreased NK cells		AR	Defect in the JAK3 signaling kinase
IL-7Rα deficiency		Markedly decreased		Normal or increased	Decreased	Normal NK cells		AR	Defect in the IL-7R α-chain
CD45 deficiency		Markedly decreased		Normal	Decreased	Normal γδ T cells		AR	CD45 defect
CD3δ/CD3ε/CD3ζ deficiency		Markedly decreased		Normal	Decreased	Normal NK cells		AR	Defect in CD3δ/CD3ε/CD3ζ chains of the antigen-recognizing T-cell receptor
2. T-B- SCID*
RAG 1/2 deficiency		Markedly decreased		Markedly decreased	Decreased	Defective VDJ recombination		AR	Complete defect of recombination-activating genes (RAG) 1 or 2
DCLRE1C (Artemis) deficiency		Markedly decreased		Markedly decreased	Decreased	Defective VDJ recombination, radiation sensitivity		AR	Defect in the DNA Repair protein (Artemis)
Adenosine deaminase (ADA) deficiency		Absent from birth (null Mutations) or progressive decrease		Absent from birth or progressive decrease	Progressive decrease	Defective VDJ recombination, radiation sensitivity		AR	Lack of ADA, elevated lymphotoxic metabolites (dATP, S-adenosylhomocysteine)
Reticular dysgenesis		Markedly decreased		Normal or decreased	Decreased	Granulocytopenia, thrombocytopenia		AR	Impaired maturation of T, B, and myeloid cells (stem cell defect)
3. Omenn syndrome		Present, limited heterogeneity		Normal or decreased	Decreased, excluding elevated IgE	Erythroderma, eosinophilia, adenopathy, hepatosplenomegaly		AR	Impaired maturation of T, B, and myeloid cells (stem cell defect)
4. DNA ligase IV deficiency		Decreased		Decreased	Decreased	Microcephaly, facial dysmorphism, radiation sensitivity		AR	DNA ligase IV defect, impaired non-homologous end joining (NHEJ)
5. Cernunnos/XLF deficiency		Decreased		Decreased	Decreased	Microcephaly, intrauterine growth restriction, radiation sensitivity		AR	Cernunnos defect, impaired non-homologous end joining (NHEJ)
6. CD40 Ligand deficiency		Normal		IgM and IgD memory B cells present, but others often absent	IgM elevated or normal, other isotypes decreased	Neutropenia, thrombocytopenia, hemolytic anemia, Liver and biliary tract disease, opportunistic infections		XL	CD40 ligand (CD40L) defect, impaired signaling in B cells and dendritic cells
7. CD40 deficiency		Normal		IgM and IgD B cells present, but other isotypes absent	IgM elevated or normal, other isotypes decreased	Neutropenia, gastrointestinal and liver diseases, opportunistic infections		AR	CD40 defect, impaired signaling in B cells and dendritic cells
8. Purine nucleoside phosphorylase (PNP) deficiency		Progressive decrease		Normal	Normal or decreased	Autoimmune hemolytic anemia, neurological disorders		AR	Lack of PNP, T-cell and neurological defects due to elevated toxic metabolites (dGTP)
9. CD3γ deficiency		Normal (decreased TCR expression)		Normal	Normal			AR	CD3γ defect
10. CD8 deficiency		CD8 absent, normal CD4 cells		Normal	Normal			AR	CD8 α-chain defect
11. ZAP-70 deficiency		Decreased CD8, normal CD4 cells		Normal	Normal			AR	ZAP-70 signaling kinase defect
12. Calcium channel deficiency	Normal count, impaired TCR-mediated activation			Normal count	Normal	Autoimmune diseases, anhidrotic ectodermal Dysplasia, non-progressive myopathy		AR	Defect in Orai1, a calcium channel component
13. MHC class I deficiency	Decreased CD8, normal CD4 cells			Normal	Normal	Vasculitis		AR	Mutations in TAP1, TAP2, and TAPBP (tapasin) genes
14. MHC class II deficiency	Normal count, decreased CD4 cell count			Normal	Normal or decreased			AR	Mutations in METABOLISM/31.html">Transcription factors for MHC class II Proteins (CIITA, RFX5, RFXAP, RFXANK genes)
15. Winged helix (nude) deficiency	Markedly decreased			Normal	Decreased	Alopecia, abnormal thymic epithelium (similar to nude mice)		AR	Defect in the transcription factor encoding the FOXN1 Gene, which is mutated in nude mice
16. CD25 deficiency	Normal or moderately decreased			Normal	Normal	Lymphoproliferation (lymphadenopathy, hepatosplenomegaly), autoimmune diseases (may resemble IPEX syndrome), impaired T-cell proliferation		AR	IL-2R α-chain defect
17. STAT5b deficiency	Moderately decreased		Normal		Normal		Growth Hormone-insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial Pneumonia	AR	STAT5B gene defect, impaired development and function of γδ T cells, Tregs, and NK cells, impaired T-cell proliferation

Note: XL - X-linked inheritance; AR - Autosomal Recessive Inheritance; MHC - Major Histocompatibility Complex; *atypical cases of SCID may present with the presence of T cells due to hypomorphic mutations or somatic mutations in T-cell progenitors.

Table 57. Antibody Deficiencies

Disease			Serum IMMUNOGLOBULINS	Associated features	Inheritance		Genetic defect / predominant pathogenesis
1. Marked decrease in levels of all serum immunoglobulin isotypes with a profound reduction in or absence of B cells
BTK deficiency			Levels of all isotypes decreased	Severe bacterial infections, normal pro-B-cell count	XL		BTK mutations
μ-heavy chain deficiency			Levels of all isotypes decreased	Severe bacterial infections, normal pro-B-cell count	AR		μ-heavy chain mutations
λ5 deficiency			Levels of all isotypes decreased	Severe bacterial infections, normal pro-B-cell count	AR		λ5 mutations
Igα deficiency			Levels of all isotypes decreased	Severe bacterial infections, normal pro-B-cell count	AR		Igα mutations
Igβ deficiency				Severe bacterial infections, normal pro-B-cell count	AR		Igβ mutations
BLNK deficiency				Severe bacterial infections, normal pro-B-cell count	AR		BLNK mutations
Thymoma with immunodeficiency				Infections, decreased pro-B-cell count	None		Unknown
Myelodysplasia				Infections, decreased pro-B-cell count	Variable		May include chromosome 7 monosomy, trisomy 8, or dyskeratosis congenita
2. Marked decrease in serum IgG and IgA levels with normal, low, or very low B-cell counts
Common variable immunodeficiency disorders*			Low IgG and IgA; variable IgM	All patients experience recurrent bacterial infections. Clinical phenotype is heterogeneous: autoimmunity, lymphoproliferative, and/or granulomatous diseases	About 10% have a familial history (AR or AD)		Alterations in TACI, BAFFR, and Msh5 genes may contribute to polymorphism**
ICOS deficiency			Low IgG and IgA; normal IgM		AR		ICOS mutations
CD19 deficiency			Levels of all isotypes decreased		AR		CD19 mutations
XLP1***			Levels of all isotypes may be decreased	Some patients present with antibody deficiency, although most manifest severe Epstein-Barr virus infection or lymphoma	XL		SH2D1A mutations
3. Severe decrease in serum IgG and IgA levels with normal/decreased IgM levels and a normal B-cell count
CD40L deficiency****			IgG and IgA decreased; IgM may be normal or decreased; B-cell count may be normal or elevated	Opportunistic infections, neutropenia, autoimmune diseases	XL		CD40L mutations (also known as TNFSF5 or CD154)
CD40 deficiency****			Low IgG and IgA; normal or elevated IgM	Opportunistic infections, neutropenia	AR		CD40 mutations (also known as TNFRSF5)
AID deficiency			IgG and IgA decreased; IgM elevated	Lymph node and germinal center enlargement	AR		AICDA Gene Mutations
UNG deficiency			IgG and IgA decreased; IgM elevated	Lymph node and germinal center enlargement	AR		UNG gene mutations
4. Isotype or light chain deficiencies with a normal B-cell count
Immunoglobulin heavy chain deletion			One or more IgG subclasses and/or IgA, as well as IgE, may be absent	May be asymptomatic	AR		Chromosome 14q32 deletion
κ-chain deficiency			All immunoglobulins possess κ light chains	Asymptomatic	AR		Mutations in the kappa (constant) chain gene
Isolated IgG subclass deficiency			Decreased level of one or more IgG subclasses	Usually asymptomatic; recurrent viral and/or bacterial infections may occur	Variable		Unknown
IgA deficiency associated with IgG subclass deficiency			Decreased IgA level along with decreased levels of one or more IgG subclasses	Recurrent bacterial infections in the majority of patients	Variable		Unknown
Selective IgA deficiency			Decreased or absent IgA level	Usually asymptomatic; may present with recurrent infections accompanied by a poor antibody response to carbohydrate Antigens, allergic, or autoimmune diseases. Individual cases progress to SCID, and some occur concurrently with SCID	Variable		Unknown
	5. Specific antibody deficiency with normal immunoglobulin concentrations and a normal B-cell count
		Normal		Inability to produce Antibodies against specific antigens	Variable	Unknown
	6. Transient hypogammaglobulinemia of infancy with a normal B-cell count
		Decreased IgG and IgA levels		Moderately severe recurrent bacterial infections	Variable	Unknown

Note: XL - X-linked inheritance; AR - autosomal recessive inheritance; AD - Autosomal dominant inheritance; BTK - Bruton Tyrosine kinase; BLNK - B-cell linker protein; AID - activation-induced cytidine deaminase; UNG - uracil-DNA glycosylase; ICOS - inducible costimulator; Ig(k) - immunoglobulin type with kappa light chains. *Common variable immunodeficiency disorders: several distinct clinical phenotypes exist, representing different diseases with diverse immunopathogenesis; alterations in TACI, BAFFR, and Msh5 sequences may represent various polymorphisms. **Disease-causing effects were identified in homozygotes with TACIC140R and A181E mutations. ***XLP1 - X-linked lymphoproliferative syndrome. ****CD40L deficiency (X-linked hyper-IgM syndrome) and CD40 deficiency.

Table 58. Immunodeficiency Syndromes

Disease	Circulating T cells			Circulating B cells	Serum immunoglobulins		Associated features	Inheritance	Genetic defects / predominant pathogenesis
1. Wiskott-Aldrich syndrome (WAS)
	Progressive decrease			Normal	Decreased IgM level: particularly low antibody levels to Polysaccharides; frequently decreased IgA and IgE concentrations		Thrombocytopenia with small platelets; eczema; lymphomas; autoimmune diseases; IgA nephropathy; bacterial and viral infections; XL thrombocytopenia is a mild form of WAS, XL neutropenia is caused by missense mutations in the GTPase-binding domain of WASP	XL	WASP mutations, cytoskeletal defects affecting hematopoietic stem cell derivatives
2. DNA repair defects
Ataxia-telangiectasia	Progressive decrease			Normal	Frequently decreased IgA, IgE, and IgG subclass levels; elevated IgM monomer levels; reduced antibody Variability		Ataxia; telangiectasia; elevated α-fetoprotein concentration; lymphoreticular and other tumors; increased sensitivity to X-irradiation, chromosomal instability	AR	ATM mutation, Cell Cycle checkpoint impairment, and DNA double-strand break repair defects
Ataxia-telangiectasia-like disorder (ATLD)	Progressive decrease			Normal	Frequently decreased IgA, IgM, and IgG subclass levels; elevated IgM monomer levels; reduced antibody variability		Moderate ataxia, markedly increased radiosensitivity	AR	Hypomorphic MRE11 mutation, cell cycle checkpoint impairment, and DNA double-strand break repair defects
Nijmegen breakage syndrome	Progressive decrease			Normal	Frequently decreased IgA, IgM, and IgG subclass levels; elevated IgM monomer levels; reduced antibody variability		Microcephaly, bird-like facies, lymphomas, sensitivity to ionizing radiation, chromosomal instability	AR	Hypomorphic NBS1 (nibrin) mutation, cell cycle checkpoint impairment, and DNA double-strand break repair defects
Bloom syndrome	Normal			Normal	Decreased		Chromosomal instability, Bone Marrow failure, leukemias, lymphomas, short stature, bird-like facies, sun-induced telangiectasias sensitivity	AR	BLM mutation, a RecQ-like helicase
3. Thymic defects
DiGeorge anomaly	Decreased or normal; frequently progressive normalization			Normal	Normal or decreased		Hypoparathyroidism, conotruncal Heart defects, facial anomalies, 22q11 (or 10p) deletion in some patients	De novo defect or AD	Gene defect disrupting thymic development in 90% of cases; TBX1 transcription factor mutation
4. Immuno-osseous dysplasias
Cartilage-Hair hypoplasia	Decreased or normal*			Normal	Normal and decreased, reduced antibody variability		Dwarfism with Metaphyseal Dysostosis, sparse hair, anemia, neutropenia, susceptibility to lymphoma and Cancer, impaired Spermatogenesis, intestinal neuronal dysplasia	AR	RMRP mutation (RNase MRP RNA)
Schimke syndrome	Decreased			Normal	Normal		Short stature, Spondyloepiphyseal Dysplasia, intrauterine growth restriction, nephropathy	AR	SMARCAL1 mutation
5. Hyper-IgE syndromes (HIES)
Job syndrome (autosomal dominant HIES)	Normal			Normal	Elevated IgE content		Recurrent skin abscesses and pneumonia, frequently caused by S. aureus, eczema, nail candidiasis, facial coarsening - thickened skin, broad nasal tip, dental eruption disorders/delay, joint hypermobility	AD, frequently de novo mutations	STAT3 mutations
Autosomal recessive HIES with mycobacterial and viral infection	Normal			Normal	Elevated IgE content		Susceptibility to intracellular Bacteria (mycobacteria, salmonella), Fungi, and Viruses, eczema. Absence of skeletal and Connective Tissue anomalies. CNS hemorrhages, fungal and viral infections	AR	TYK2 mutation. Unknown
Autosomal recessive HIES with viral infections, CNS vasculitis/hemorrhages	Normal			Normal	Elevated IgE content		Susceptibility to intracellular bacteria (mycobacteria, salmonella), fungi, and viruses, eczema, vasculitis, CNS hemorrhages. Absence of skeletal and connective tissue anomalies	AR	Unknown
6. Chronic mucocutaneous candidiasis
	Normal			Normal	Normal		Chronic mucocutaneous candidiasis; impaired delayed-type hypersensitivity to Candida antigens; autoimmune diseases; absence of ectodermal dysplasia	AD, AR, sporadic	Unknown
7. Veno-occlusive disease of the liver with immunodeficiency (VODI)
		Normal (decreased memory T cells)	Normal (decreased memory B cells)		Decreased IgG, IgA, IgM	Veno-occlusive liver disease, Pneumocystis pneumonia, thrombocytopenia, hepatosplenomegaly		AR	SP110 mutation
8. Hoyeraal-Hreidarsson syndrome
		Progressive decrease	Progressive decrease		Variable	Intrauterine growth restriction, microcephaly, gastrointestinal disorders, pancytopenia, decreased number and functional activity of NK cells		XL	Dyskerin mutation

Note: *patients with cartilage-hair hypoplasia may also present with typical SCID or Omenn syndrome.

Table 59. Diseases Causing Immune Dysregulation

Disease	Circulating T cells	Circulating B cells	Serum immunoglobulins	Associated features	Inheritance	Genetic defects / predominant pathogenesis
1. Immunodeficiencies with hypopigmentation
Chediak-Higashi syndrome	Normal	Normal	Normal	Partial albinism, low activity of NK cells and cytotoxic lymphocytes, enhanced acute-phase responses, encephalopathic reactions	AR	LYST defect, impaired lysosomal trafficking
Griscelli syndrome, type 2	Normal	Normal	Normal	Partial albinism, low activity of NK cells and cytotoxic lymphocytes, enhanced acute-phase responses, encephalopathic reactions	AR	Defects in RAB27A, which encodes a GTPase in secretory vesicles
Hermansky-Pudlak syndrome, type 2	Normal	Normal	Normal	Partial albinism, neutropenia, increased bleeding diathesis, low activity of NK cells and cytotoxic lymphocytes	AR	Mutations in the AP3B1 gene encoding the β subunit of the AP-3 complex
2. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes
Perforin deficiency	Normal	Normal	Normal	Severe inflammation, fever, decreased activity of NK cells and cytotoxic lymphocytes	AR	PRF1 defect, perforin is the major cytolytic protein
Munc13-4 deficiency	Normal	Normal	Normal	Severe inflammation, fever, decreased activity of NK cells and cytotoxic lymphocytes	AR	MUNC13D defect, required for vesicle priming and docking
Syntaxin 11 deficiency	Normal	Normal	Normal	Severe inflammation, fever, decreased activity of NK cells and cytotoxic lymphocytes	AR	STX11 defect, required for vesicle transport and docking
3. X-linked lymphoproliferative syndrome (XLP)
XLP 1	Normal	Normal or decreased	Normal or low immunoglobulins	Clinical and immunological disorders triggered by Epstein-Barr virus infection, including hepatitis, aplastic anemia, lymphoma	XL	SH2D1A defect encoding an adaptor protein that regulates Intracellular Signaling
XLP 2	Normal	Normal or decreased	Normal or low immunoglobulins	Clinical and immunological disorders triggered by Epstein-Barr virus infection, including Splenomegaly, hepatitis, hemophagocytic syndrome, lymphoma	XL	XIAP defect encoding an apoptosis inhibitor
4. Syndromes with autoimmune diseases
Autoimmune lymphoproliferative syndrome (ALPS)
CD95 (Fas) defect, ALPS type 1a	Elevated levels of double-negative T cells (CD4-CD8-)	Normal	Normal or elevated	Splenomegaly, adenopathy, autoimmune hemocytopenia, lymphocyte apoptosis defect, high risk of lymphomas	AD (rarely severe AR)	TNFRSF6 defect, cell surface apoptosis receptor. Additionally, somatic mutations can cause a similar phenotype, ALPS type 1a (somatic)
CD95L (FasL) defect, ALPS type 1b	Elevated levels of double-negative T cells (CD4-CD8-)	Normal	Normal	Splenomegaly, adenopathy, autoimmune hemocytopenia, lymphocyte apoptosis defect, lupus	AD AR	TNFSF6 defect, ligand for the CD95 apoptosis receptor
Caspase 10 defect, ALPS type 2b	Elevated levels of double-negative T cells (CD4-CD8-)	Normal	Normal	Splenomegaly, adenopathy, autoimmune hemocytopenia, lymphocyte apoptosis defect	AD	CASP10 defect, an enzyme in the intracellular apoptotic pathway
Caspase 8 defect, ALPS type 2b	Slightly elevated levels of double-negative T cells (CD4-CD8-)	Normal	Normal or decreased	Adenopathy, splenomegaly, recurrent bacterial and viral infections, defective apoptosis and lymphocyte activation	AD	CASP8 defect, an enzyme in the intracellular apoptotic and activation pathways
N-Ras activation defect, ALPS	Elevated levels of double-negative T cells (CD4-CD8-)	Expansion of CD5+ B cells	Normal	Adenopathy, splenomegaly, leukemia, lymphoma, defective lymphocyte apoptosis following IL-2 withdrawal	AD	N-Ras defect, encoding a GTP-binding protein involved in various signaling Functions; activating mutations impair mitochondrial apoptosis
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy	Elevated levels of CD4+ cells	Normal	Normal	Autoimmune disease affecting the parathyroid, adrenal, and other Endocrine glands along with candidiasis, enamel hypoplasia, and other anomalies	AR	AIRE defect encoding a transcription regulator. Required for thymic tolerance
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome	Deficiency of CD4+ CD25+ FOXP3+ regulatory T cells	Normal	Elevated IgA and IgE levels	Autoimmune diarrhea, early-onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema	XL	FOXP3 defect encoding a T-cell transcription factor

Table 60. Congenital Defects in Phagocyte Number and/or Function

		Disease	Affected cells	Affected functions	Associated features		Inheritance	Genetic defects / predominant pathogenesis
1-3		Severe congenital neutropenia	N N N	Myeloid differentiation Myeloid differentiation Myeloid differentiation	Subgroups with myelodysplasia. B-/T-lymphopenia. G-CSF-refractory neutropenia		AD AD AD	ELA2: impaired Elastase transport. GFI1: elastase repression. G-CSFR
4		Kostmann disease	N	Myeloid differentiation			AR	HAX1: apoptosis control
5		Cyclic neutropenia	N	?	Fluctuations in other leukocyte and platelet counts		AD	ELA2: impaired elastase transport
6		X-linked neutropenia / myelodysplasia	N+M	?	Monocytopenia		XL	WASP: Actin Cytoskeleton regulation
7		p14 deficiency	N+L Melanocytes	Endosomal biogenesis	Neutropenia. Hypogammaglobulinemia, decreased CD8 cytotoxicity, partial albinism, developmental delay		AR	LAMTOR2 (p14): endosomal adaptor protein
8		Leukocyte adhesion deficiency, type 1 (LAD-1)	N+M L+NK	Adhesion, chemotaxis, endocytosis, T/NK cytotoxicity	Delayed umbilical cord Separation, skin ulcers. Periodontitis, leukocytosis		AR	ITGB2: adhesion protein
9		LAD, type 2	N+M	Rolling, chemotaxis	LAD-1 features and Bombay (hh) Blood group, intellectual disability		AR	SLC35C1 (FUCT1): GDP-fucose transporter
10		LAD, type 3	N+M L+NK	Adhesion	LAD-1 features and bleeding diathesis		AR	FERMT3 (kindlin-3): defective Rap1-mediated activation of β1-3 Integrins
11		Rac2 deficiency	N	Adhesion, chemotaxis, O₂^- production	Impaired wound healing, leukocytosis		AD	RAC2: actin cytoskeleton regulation
12		β-actin deficiency	N+M	Motility	Intellectual disability, short stature		AD	ACTB: cytoplasmic actin
13		Localized juvenile periodontitis	N	Formyl peptide-induced chemotaxis	Periodontitis only		AR	FPR1: chemokine receptor
14		Papillon-Lefèvre syndrome	N+M	Chemotaxis	Periodontitis, palmoplantar keratoderma		AR	CTSC: cathepsin C activation of Serine proteases
15		Specific granule deficiency	N	Chemotaxis	Bilobed neutrophils	AR		CEBPE: myeloid transcription factor
16		Shwachman-Diamond syndrome	N	Chemotaxis	Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia	AR		SBDS
17		X-linked chronic granulomatous disease (CGD)	N+M	Microbicidal activity (defective O₂^- production)	McLeod phenotype	XL		CYBB: electron transport protein (gp91phox)
18-20		Autosomal chronic granulomatous disease (CGD)	N+M	Microbicidal activity (defective O₂^- production)		AR		CYBA: electron transport protein (p22phox) NCF1: adaptor protein (p47phox) NCF2: activating protein (p67phox)
21		Neutrophil glucose-6-phosphate dehydrogenase deficiency	N+M	Microbicidal activity (defective O₂^- production)	Hemolytic anemia	XL		G6PD: NADPH production
22		IL-12 and IL-23 receptor β1 chain deficiency	L+NK	IFN-γ secretion	Susceptibility to mycobacteria and salmonella	AR		IL12RB1: IL-12 and IL-23 receptor β1 chain
23		IL-12p40 deficiency	M	IFN-γ secretion	Susceptibility to mycobacteria and salmonella	AR		IL12B (IL-12p40 subunit): IL-12/IL-23 production
24		IFN-γ receptor 1 deficiency	M+L	IFN-γ binding and signaling	Susceptibility to mycobacteria and salmonella	AR, AD		IFNGR1: IFN-γR binding chain
	25	IFN-γ receptor 2 deficiency	M+L	IFN-γ binding and signaling	Susceptibility to mycobacteria and salmonella	AR		IFNGR2: IFN-γR signaling chain
	26	STAT1 deficiency (two forms)	M+L	IFN-α/β/γ signaling. IFN-γ signaling	Susceptibility to mycobacteria, salmonella, and viruses. Susceptibility to mycobacteria and salmonella	AR AD		STAT1 STAT1

Note: N - neutrophils; M - monocytes/macrophages; L - lymphocytes; STAT1 - signal transducer and activator of transcription 1.

Table 61. Defects of Innate Immunity

Disease	Affected cells	Functional defects	Associated features	Inheritance	Genetic defects / predominant pathogenesis
Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)	Lymphocytes and monocytes	NF-κB signaling pathway	Anhidrotic ectodermal dysplasia, specific antibody deficiency (impaired response to polysaccharides), various infections (mycobacterial and pyogenic)	XR	NEMO (IKBKG) mutations: NF-κB activation modulator
Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)	Lymphocytes and monocytes	NF-κB signaling pathway	Anhidrotic ectodermal dysplasia, T-cell deficiency, various infections	AD	IKBKA mutation leading to impaired NF-κB activation
Interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency	Lymphocytes and monocytes	TIR-IRAK signaling pathway	Bacterial infections (caused by pyrogens)	AR	IRAK4 mutation: component of the TLR signaling pathway
WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis)	Granulocytes and lymphocytes	Enhanced response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)	Hypogammaglobulinemia, decreased B-cell count, profound neutropenia, warts, human papillomavirus infection	AD	CXCR4 mutations: receptor for CXCL12
Epidermodysplasia verruciformis	Keratinocytes and leukocytes	?	Infections caused by human papillomavirus (beta group) and skin cancer	AR	EVER1, EVER2 mutations
Herpes simplex virus encephalitis	CNS resident cells, epithelial cells, and leukocytes	UNC93B1-dependent induction of IFN-α/β/γ	Encephalitis and Meningitis caused by herpes simplex virus type 1	AR	UNC93B1 mutations
Herpes simplex virus encephalitis	CNS resident cells, epithelial cells, dendritic cells, cytotoxic lymphocytes	TLR3-dependent induction of IFN-α/β/γ	Encephalitis and meningitis caused by herpes simplex virus type 1	AD	TLR3 mutations

Note: NFkB - nuclear factor kappa B; TIR - Toll and interleukin-1 receptor; TLR - Toll-like receptor.

Table 62. Autoinflammatory disorders

Disease	Affected cells	Functional defects	Associated features	Inheritance	Genetic defects
Familial Mediterranean fever	Mature granulocytes, cytokine-activated monocytes	Reduced pyrin production allows ASC-induced IL-1 Processing and inflammation accompanied by subclinical serous involvement; reduced macrophage apoptosis	Recurrent fever, serositis, inflammatory response to colchicine. Predisposition to vasculitis and inflammatory bowel disease	AR	MEFV mutations
TNF receptor-associated periodic syndrome (TRAPS)	Polymorphonuclear cells, monocytes	Mutations in the 55-kD TNF receptor leading to intracellular receptor retention or decreased soluble TNF-binding cytokine receptor	Recurrent fever, serositis, rash, ocular or joint inflammation	AD	TNFRSF1A mutations
Hyper-IgD syndrome		Mevalonate kinase deficiency leading to impaired Cholesterol synthesis; disease pathogenesis remains unclear	Periodic fever and leukocytosis with high IgD levels	AR	MVK mutations
Muckle-Wells syndrome (Muckle-Wells)*	Polymorphonuclear cells, monocytes	Cryopyrin defect involved in apoptosis, NFkB signaling, and IL-1 processing	Urticaria, sensorineural Hearing loss, amyloidosis. Responsive to IL-1R/agonist (anakinra)	AD	Mutations in CIAS1 (also known as PYPAF1 and NALP3)
Familial cold autoinflammatory syndrome*	Polymorphonuclear cells, chondrocytes	See above	Non-pruritic urticaria, Arthritis, chills, fever, and leukocytosis following cold exposure. Responsive to IL-1R/agonist (anakinra)	AD	CIAS1 mutations
Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurological, cutaneous, and articular syndrome (CINCA)*	Polymorphonuclear cells, chondrocytes	See above	Neonatal rash, chronic meningitis, arthropathy with fever, and inflammatory response to IL-1R/agonist (anakinra)	AD	CIAS1 mutations
Pyogenic sterile arthritis, Pyoderma gangrenosum, and acne (PAPA) syndrome	Hematopoietic Tissues, activated T cells	Impaired actin reorganization leading to defective physiological signaling during the inflammatory response	Destructive arthritis, inflammatory skin rash, myositis	AD	PSTPIP1 mutations (also known as CD2BP1)
Blau syndrome	Monocytes	Mutations in the nucleotide-binding domain of CARD15, potentially disrupting lipopolysaccharide interaction and NFkB signaling	Uveitis, granulomatous synovitis, camptodactyly, rash, cranial neuropathy, Crohn's disease in 30% of patients	AD	NOD2 mutations (also known as CARD15)
Chronic recurrent multifocal Osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)	Neutrophils, bone marrow cells	Undefined	Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, inflammatory skin disorders	AR	LPIN2 mutations

Note: *all three syndromes are associated with similar CIAS1 mutations; the disease phenotype in individual patients depends on the modifying Effects of Other genes or environmental factors.

ASC - apoptosis-associated speck-like protein containing a caspase recruitment domain; CARD - caspase recruitment domain; CD2BP1 - CD2-binding protein 1; PSTPIP1 - Proline-serine-Threonine phosphatase-interacting protein 1; CIAS1 - cold-induced autoinflammatory syndrome 1.

Hyper-IgE syndrome (Job's syndrome)

Specific defect. Decreased interferon-gamma production by T-helper 1 cells. Elevated IgE production >1000 IU/mL in patients with a history of dermatitis and recurrent deep 'cold' pyogenic infections; histamine release impairs neutrophil chemotaxis.

Clinical features. Characterized by recurrent 'cold' abscesses of the skin, subcutaneous tissue, and Lymph Nodes, recurrent 'cold' purulent otitis media, and chronic eczema. These abscesses are termed 'cold' due to the absence of a normal inflammatory response. Severe episodes of acute pneumonia, including destructive pneumonia (in 50%) progressing to pneumatocele (in 50%), and liver abscesses represent particular dangers. Characteristic somatic signs include atypical 'atopic dermatitis', dysplastic facial features, and spontaneous fractures of long bones (Table 51).

Immunological evaluation reveals impaired neutrophil chemotaxis with preserved engulfment and digestive activity. Serum IgE levels are markedly elevated (>1000 IU/mL), which may be accompanied by eosinophilia. According to modern data, a major defect in this pathology is the inability of T-helper 1 cells to produce interferon-gamma. This leads to enhanced T-helper 2 function and IgE hyperproduction. IgE triggers histamine release, which blocks The Development of inflammation; furthermore, histamine inhibits neutrophil chemotaxis, representing another characteristic hallmark of Job's syndrome.

Symptomatic and antibacterial treatment. Patients with Job's syndrome require continuous (lifelong) antibiotic therapy, necessary even during periods of remission from infectious manifestations, combined with antifungal agents adjusted for age.

Atopic dermatitis is treated with steroid ointments and creams (hydrocortisone, Celestoderm, Betnovate, Advantan, Elocon, Synalar, etc.).

Chronic Granulomatous Disease (CGD)

(ICD-10 Code D89.8)

CGD is a primary immunodeficiency of the phagocytic Lineage characterized by an inherited impairment of neutrophil bactericidal function, fundamentally caused by the inability of neutrophils to generate reactive oxygen species required for the oxygen-dependent killing of phagocytized microorganisms.

Chronic granulomatous disease involves dysfunction of the phagocyte NADPH oxidase system, leading to incomplete phagocytosis and granuloma formation.

The predominant inheritance pattern is X-linked (80% of patients are male), although an autosomal recessive form of the disease also exists.

Clinical manifestations: The disease typically begins in early childhood, though onset is occasionally delayed until adolescence. Purulent infections of the skin, subcutaneous adipose tissue, and lymph nodes, as well as destructive pneumonia, osteomyelitis, and liver abscesses, are observed. Recurrent infections caused by catalase-producing microorganisms (Staphylococcus aureus, Serratia, Escherichia, Pseudomonas) are characteristic. Various fungal infections are observed, including Aspergillus species causing pneumonia or disseminated infections, and Candida primarily affecting mucous membranes and soft tissues. The clinical picture includes growth retardation and BCGitis. Rhinitis, dermatitis, diarrhea, perianal abscesses, stomatitis, osteomyelitis, Brain abscesses, and gastrointestinal/genitourinary tract obstruction due to granuloma formation are also noted.

Immunological tests: Chemiluminescence and NBT tests with granulocytes. Hemogram alterations indicative of chronic infections (Tables 50, 51).

Immunological evaluation via the NBT test reveals impaired oxygen-dependent metabolism in neutrophils. B- and T-cell functions, as well as complement levels, remain within normal limits (Table 56).

Pharmacotherapy. Patients with CGD require continuous (lifelong) antibacterial therapy, necessary even during periods of remission of infectious symptoms. Patients are permanently prescribed trimethoprim-sulfamethoxazole (Septrin, Bactrim, Oriprim)—due to its ability to penetrate cell membranes and enhance phagocytic bactericidal activity—or rotating broad-spectrum oral antibiotics (Cephalosporins, semi-synthetic Penicillins, oxyquinolones, etc.) combined with antifungals. Antifungal therapy: for Aspergillus infections, Amphotericin B (Fungizone) 1 mg/kg/day for 6 months; for Candida infections, itraconazole (Sporanox) at age-appropriate dosages. Upon the development of infectious complications, patients generally require parenteral antimicrobial therapy, the intensity of which may involve simultaneous administration of 2–3 drugs for many months (in cases of lung and internal organ abscesses). Fungal lesions of the Lungs and Internal Organs are frequent infectious complications, in which case parenteral antifungal therapy is employed. Topical antiseptics (brilliant green, chlorhexidine) are used as indicated.

As an example of the Immune Response in a primary immunodeficiency of the phagocytic lineage, we present the clinical case of patient S., 19 years old, suffering from a congenital phagocytic system immunodeficiency—chronic granulomatous disease—who was under observation at the City Pediatric Immunology Center.

Patient S., 19 years old, has a history since childhood of frequent pneumonias, Pyelonephritis, cystitis, recurrent chronic furunculosis, and purulent lymphadenitis. Examination reveals infiltrates (granulomas) measuring 1×1.5 cm beneath the skin of the torso and extremities. She underwent surgery for an abscess in the right gluteal region and exhibits grade III dysbiosis. Diagnosis: chronic granulomatous disease.

Immunogram of patient S., 19 years old (Table 63), demonstrates neutrophilic leukocytosis, normal counts and ratios of T AND B lymphocytes, immunoglobulin concentrations within normal limits, a slight increase in IgM levels, and a drastic reduction in the NBT test, including its reserve capacity, indicating profound impairment of phagocytic activity.

Treatment:

1) Roncoleukin 500,000 IU subcutaneously every 3 days, 5 injections;

2) interferon gamma 1 million IU IM 3 times a week, long-term;

3) co-trimoxazole (Bactrim) 1 tablet contains 80 mg of trimethoprim, 400 mg of sulfamethoxazole (pediatric - 20/100 mg respectively); 1 tab. 1-2 times daily, on an ongoing basis, long-term;

4) itraconazole 100 mg every other day, long-term;

5) Gene Therapy - IV infusion of stem cells with a normal gp91phox gene to the patient.

Working with garden limestone (leaves, branches, and tree bark containing fungal spores) is contraindicated.

Table 63. Immunogram of patient S., aged 19

Parameter		Result		Reference range
Hemoglobin		130		F - 115 - 145, M - 132 - 164 g/L
Erythrocytes		3,8		F - 3,7 - 4 ,7, M - 4,0 - 5,1x1012 /L
Platelets		240		150 - 320x109/L
ESR		24		2 - 15 mm /h
Leukocytes		15		4 - 9x109 /L
Neutr.	Band	Seg.	Eos.	Bas.	Mon.	Lymph.	LGL	Plas.
43 - 71 %	1 - 4 %		0,5 - 5%	0 - 1%	3 - 9%	25 - 37%	1-5%	0 - 1%
2000-6500	80-400		80-370	20-80	90-720	1600-3000	80-500	20-80
69	6	58	2	1	5	23	1
10350	900	9450	300	150	750	3450	150
Immunological parameters		Result	Reference range	Immunological parameters			Result	Reference range
Immunological parameters		Result	(SI units)	Immunological parameters			Result	(SI units)
T-lymph.	%	62	50 - 80	Ig G			15,0	8,0-18,0
CD-3	Absolute count	2139	1000-2200	Ig G				g/L
T-help.	%	35	33-46	Ig M			2,2	0,2-2,0 g/L
CD-4	Absolute count	1207	309-1571	Ig M
T-suppr.	%	25	17-30	Ig A			2,8	0,3-3,0 g/L
CD-8	Absolute count	862	282-999	Ig A
IRI	CD-4/CD-8	1,4	1,4-2,0	CIC			55	30 - 50 units
				CIC				opt. density
NK cells CD-16	%	21	12 - 23	Phagocytic		PN	35	60 - 80%
NK cells CD-16	Absolute count	724	72-543	activity		PI	0,9	1,5 - 3,5
B-lymph.	%	18	17-31	NBT test		spon.	2	up to 10%
CD-22	Absolute count	621	109-532			ind.	6	_-
SLBT	spon.	_-	up to 10%			res.	4	^h16%
	ind.	10	50-70%	Complement		CH-50	50	30 - 60
								hem. units/mL

Adhesion molecule expression deficiency

Specific defect. Impaired phagocyte adhesion and chemotaxis resulting from decreased expression of the beta subunit (95 KD) of the LFA-1, p150, 95 adhesion molecules.

Chromosomal localization of the defect: 21q 22.3.

Impaired expression of adhesion molecules can be either genetically determined or acquired, specifically associated with The Use of medications such as salicylates, ethanol, adrenaline, and corticosteroids. Abnormal expression of adhesion molecules may also be observed in patients with Diabetes Mellitus, myotonic dystrophy, extensive Burns, and in neonates.

Clinical and laboratory findings: 1) recurrent skin abscesses; 2) gastric and intestinal lesions; 3) pneumonia; 4) cellulitis; 5) leukocytosis (15-20 x106 per 1 L); 6) absence of pus; 7) wide spectrum of causative microorganisms (Tables 50, 51).

Treatment: antibacterial, symptomatic.

Table 64 presents the main adhesion molecules whose expression defects can cause recurrent infectious diseases.

Table 64. Adhesion molecules On the surface of phagocytic cells involved in the execution of their functions

Adhesion molecules	Cells expressing the molecules	Functions involving the molecules
LFA-1	Neutrophils, monocytes, lymphocytes	Attachment to endothelial cells (chemotaxis, adhesion)
Mo-1	Large granular lymphocytes	Binding to C3bi(CR3) (adhesion, complement binding)
P150,95	Monocytes, neutrophils, B cells	Binding to C3d(CR2) (complement binding)
CR1	Monocytes, neutrophils	Binding to C3b(CR1) (complement binding)

Deficiency of complement system components

Primary deficiency of complement system components is less common than other primary immunodeficiencies, accounting for only 1% of the total number of primary immunodeficiencies.

Genetic defects have been described for most complement components - C1q, C1r, C1s, C2, C4, C3, C5, C6, C7, C8, and C9. All of them are inherited in an autosomal recessive manner; heterozygotes can be identified during laboratory screening, showing a defective complement protein level reduced by half compared to normal values. C2 deficiency is the most frequently detected in the human population: approximately one in 100 individuals is heterozygous for this protein defect (Tables 65, 66).

The most common clinical symptom associated with defects in early complement components (C1, C2, C4) is immune complex disease. In contrast, congenital defects in late complement components (C5 through C8) are associated with recurrent gonococcal infection. C3 deficiency clinically manifests as recurrent pyogenic infection. Thus, the established clinical and immunological associations confirm Structure/19.html">The Importance of The Complement System in: 1) the elimination and/or solubilization of immune complexes; 2) antibacterial defense; 3) opsonization mechanisms.

Congenital defects of complement system inhibitors, specifically C1 inhibitor and C3b inactivator (factor I), are also clinically significant.

C1 inhibitor deficiency clinically manifests as hereditary angioedema. It is inherited in an autosomal dominant manner. Such patients are prone to recurrent attacks of skin and mucosal edema, which can be localized in any part of the body. Table 66 outlines the clinical manifestations associated with deficiencies of various complement components.

Table 65. Complement deficiencies

	Disease	Functional defects	Associated features	Inheritance	Genetic defects
	C1q deficiency	Absence of C-hemolytic activity Defective MAC*: ✵ impaired immune complex solubilization; ✵ impaired clearance of apoptotic cells	SLE-like syndrome, rheumatic diseases, infections	AR	C1q
	C1r deficiency	Absence of C-hemolytic activity Defective MAC*: ✵ impaired immune complex solubilization	SLE-like syndrome, rheumatic diseases, infections	AR	C1r*
	C1s deficiency	Absence of C-hemolytic activity	SLE-like syndrome, multiple autoimmune diseases	AR	C1s*
	C4 deficiency	Absence of C-hemolytic activity Defective MAC*: ✵ impaired immune complex solubilization; ✵ impaired HUMORAL IMMUNE RESPONSE	SLE-like syndrome, rheumatic diseases, infections	AR	C4A#
	C2 deficiency**	Absence of C-hemolytic activity Defective MAC*: ✵ impaired immune complex solubilization	SLE-like syndrome, vasculitis, polymyositis, pyogenic infections	AR	C2**
	C3 deficiency	Absence of C-hemolytic activity Defective MAC: ✵ impaired bactericidal activity; ✵ impaired humoral immune response	Recurrent pyogenic infections	AR	C3
	C5 deficiency	Absence of C-hemolytic activity Defective MAC: ✵ impaired bactericidal activity	Neisserial infections, SLE	AR	C5
	C6 deficiency	Absence of C-hemolytic activity Defective MAC: ✵ impaired bactericidal activity	Neisserial infections, SLE	AR	C6
	C7 deficiency	Absence of C-hemolytic activity Defective MAC: ✵ impaired bactericidal activity	Neisserial infections, SLE, vasculitis	AR	C7
	C8a deficiency***	Absence of C-hemolytic activity Defective MAC: ✵ impaired bactericidal activity	Neisserial infections, SLE	AR	C8b
	C8b deficiency	Absence of C-hemolytic activity Defective MAC: ✵ impaired bactericidal activity	Neisserial infections, SLE	AR	C8g
C9 deficiency		Absence of C-hemolytic activity Defective MAC: ✵ impaired bactericidal activity	Neisserial infections****	AR	C9
C1 inhibitor deficiency		Spontaneous complement activation with consumption of C4/C2 Spontaneous activation of the contact system with bradykinin generation from high-molecular-weight kininogen	Hereditary angioedema	AD	C1 inhibitor
Factor I deficiency		Spontaneous activation of The alternative pathway with consumption of C3	Recurrent pyogenic infections, Glomerulonephritis, hemolytic uremic syndrome	AR	Factor I
Factor H deficiency		Spontaneous activation of the alternative pathway with consumption of C3	Hemolytic uremic syndrome, membranoproliferative glomerulonephritis	AR	Factor H
Factor D deficiency		Absence of hemolytic activity upon alternative pathway activation	Neisserial infections	AR	Factor D
Properdin deficiency		Absence of hemolytic activity upon alternative pathway activation	Neisserial infections	XL	Properdin
Mannose-binding Protein deficiency (MBP)*****		Impaired mannose recognition Impaired hemolytic activity in the lectin pathway	Pyogenic infections with low penetrance, mostly asymptomatic	AR	MBP*****
MASP2 deficiency******		Absence of hemolytic activity in the lectin pathway	SLE syndrome, pyogenic infections	AR	MASP2
Complement receptor 3 (CR3) deficiency		See Table 66 LAD1		AR	ITGB2
Membrane cofactor protein deficiency (CD46)		Alternative pathway complement inhibitor, decreased C3b binding	Glomerulonephritis, atypical hemolytic uremic syndrome	AD	MCP
Membrane attack complex inhibitor deficiency (CD59)		Erythrocytes highly susceptible to complement-mediated lysis	Hemolytic anemia, thrombosis	AR	CD59
Paroxysmal nocturnal hemoglobinuria		Complement-mediated hemolysis	Recurrent hemolysis	Acquired X-linked mutation	PIGA

Note: *C1r and C1s genes are located 9.5 kb apart from each other, therefore C1r-deficient individuals frequently have C1s deficiency.

#Gene Duplication can lead to two active C4A genes located within 10 kb. C4 deficiency requires defects in both genes, usually resulting from a deletion. **Type 1 C2 deficiency is closely linked to HLA-A25, B18, -DR2, and the SC42 complotype (slow variant of factor B, absence of C2, type 4 C4A, type 2 C4B) and is typically found in Caucasians (1 in 10,000). It results from a 28 bp deletion leading to a premature stop codon in the C2 gene; no C2 mRNA is produced. Type 2 C2 deficiency is very rare and involves an amino acid substitution that blocks C2 secretion. ***C8-α deficiency is always associated with C8-γ deficiency. The gene encoding C8-γ is mapped to chromosome 9 and is normal. C8-γ is covalently bound to C8-α. ****The association is weaker than with C5, C6, C7, and C8 deficiencies. C9 occurs in 1 out of 1,000 Japanese individuals. *****A population study revealed no significant increase in the frequency of infection in MBL-deficient adults. ******Single patient.

Table 66. Clinical manifestations associated with deficiencies of various complement components

Complement components	Clinical manifestations
C1 inhibitor	Hereditary angioedema
C1q	High incidence of immune complex disease (systemic lupus erythematosus, glomerulonephritis)
C1r	Same
C2	»
C4	»
C3	Recurrent pyogenic infections
C5	Recurrent gonococcal (neisserial) infections, high incidence of systemic lupus erythematosus
C6	Recurrent gonococcal infections
C7	Same
C8	»
C9	Asymptomatic course
Factor I (C3b inactivator)	Recurrent pyogenic infections
Factor H	Same
Properdin	Recurrent gonococcal infections

Hereditary angioedema. A clinical example of a primary defect in the complement system is hereditary angioedema, caused by a deficiency of the first complement component inhibitor—C1 inhibitor (C1-INH). This is a relatively rare autosomal dominant disorder. It was first clinically described in 1888 by W. Osler, who noted that members of a single American family suffered for five generations from episodic Swelling that sooner or later resulted in death.

The main clinical symptom of the disease is recurrent edema of the skin and mucous membranes without signs of inflammation. The most frequent sites of edema are: 1) extremities; 2) face; 3) mucous membranes: a) Stomach and intestines; b) fauces (throat); c) Larynx.

Clinical features of the hereditary form of angioedema that distinguish it from the allergic form include: 1) limited area; 2) firm consistency; 3) pallor; 4) relative lack of pain when localized in the skin; pain, nausea, and diarrhea when the gastrointestinal mucosa is involved; 5) absence of pruritus; 6) rare presence of non-pruritic maculopapular and erythematous rash; 7) lack of association with urticaria.

Intestinal mucosal edema can cause bowel obstruction, whereas swelling of the upper respiratory mucosa may lead to asphyxiating conditions.

Factors triggering the development of edema include: 1) trauma: a) dental Procedures; b) tonsillectomy; c) endotracheal intubation; d) accidental injury; 2) physical exertion; 3) menstruation; 4) Pregnancy; 5) emotional Shock; 6) anxiety and stress. In 1/3 of cases, the precipitating factors remain unidentified. Quite often, patients report experiencing a tingling sensation or a feeling of tightness in the affected area a few hours prior to the onset of edema.

The duration of angioedema typically ranges from 24 to 72 hours. This characteristic feature can also be utilized for Differential diagnosis with allergic angioedema, which tends to resolve more rapidly.

The frequency of edema attacks varies among patients. Some individuals remain free of swelling for several years, only to experience recurrent episodes over a short period thereafter. In others, edema develops persistently. Interestingly, angioedema does not occur during the final two trimesters of pregnancy or during childbirth, for which there is currently no precise explanation.

Pathophysiological forms of the disease. Angioedema is rooted in a congenital deficiency of the C1 esterase inhibitor (C1-INH). There are two pathophysiological forms of C1-INH deficiency. In the first form, observed in the majority of patients (85–90%), There is a true quantitative deficiency of C1-INH, while its functional activity remains preserved. This pathophysiological variant is designated as classic hereditary angioedema.

The alternative form is characterized by normal—or in some cases even elevated—levels of C1-INH in 10–15% of patients, accompanied by a sharp decline in its functional activity. This pathophysiological variant is designated as variant hereditary angioedema. Both forms are inherited, and affected individuals are heterozygous for this trait.

Mechanism of hereditary angioedema. It is known that the critical level of plasma C1-INH required to maintain normal inhibitory activity is approximately 30% of that found in a healthy individual. It is also well established that functionally, C1-INH participates in Blood Coagulation and Fibrinolysis, kinin formation, and the control of complement system activation. Such extensive consumption of C1-INH occasionally creates conditions where its concentration drops below the critical threshold, triggering the clinical manifestations of angioedema. For example, trauma, which is a frequent trigger for edema, activates Hageman factor. This factor, in turn, activates plasmin, which acts as an activator of the first complement component, C1. In the absence of a sufficient amount of normally functioning C1-INH in the peripheral blood, activation of the complement system—primarily C4 and C2—is initiated, leading to subsequent edema development. Currently, it is widely accepted that the specific causative factor responsible for the edema is bradykinin, one of the kinins whose formation is induced following the activation of the second complement component, C2.

It should be noted that In addition to hereditary angioedema, there is acquired angioedema, which is characterized by a late onset and a reduced level of C1-INH while its function remains preserved. The reduction in C1-INH levels is caused either by various underlying conditions or by the development of autoantibodies against C1-INH.

Laboratory investigations. Complete blood count (if values deviate from the normal range, repeat testing once every 10 days).

Assay of C1 inhibitor and C2 and C4 complement components. Blood type and Rh factor.

Biochemical blood profile (total protein, total and direct bilirubin, ALT, AST).

Monitoring of the BLOOD COAGULATION SYSTEM once every 10 days (for patients receiving epsilon-aminocaproic acid or tranexamic acid).

For the Laboratory Diagnosis of angioedema and the Cytology/practical/136.html">DIFFERENTIAL DIAGNOSIS OF its various forms, the levels of C1-INH, C4, C2, C3, and C1 are measured (Table 67).

Table 67. Differential diagnosis of angioedema based on laboratory parameters

Complement components	Complement component levels in Various Forms of angioedema
Complement components	true	variant	acquired
C1-INH	N 30% of normal; normal activity	Normal or elevated; impaired activity	N 30% of normal; normal activity
С4-С2	Decreased	Decreased	Decreased
С3	Normal	Normal	Normal
С1	Normal	Normal	Decreased

In addition to the aforementioned hereditary angioedema with its two pathophysiological forms (true and variant) and acquired angioedema, there is also allergic angioedema, which will be discussed below.

Treatment and Prevention of hereditary angioedema. Lifestyle modification recommendations: activities associated with a risk of trauma, physical exertion, or mechanical pressure are contraindicated, including relevant occupational duties.

I. Treatment of an acute attack: fresh or fresh-frozen native plasma is administered intravenously in a single dose of at least 250-300 ml, or 5% s-aminocaproic acid (s-ACA) solution via IV drip at 100-200 ml, followed by 100 ml via drip every 4 hours, or 4 g/day orally until the exacerbation completely subsides. Instead of s-ACA, tranexamic acid can be used at 1-1.5 g orally 2-3 times a day.

For edema in the face and neck region, intravenous administration includes native plasma (250-300 ml), 5% s-ACA solution (200-300 ml), Lasix (40-80 mg), and dexasone (8-12 mg). In the event of laryngeal edema: inhalation of 0.1% adrenaline solution, 5% ephedrine solution, and beta-adrenergic agonists. The development of laryngeal edema requires hospitalization of the patient in an intensive care unit or an emergency ENT department.

The development of abdominal syndrome requires consultation with a surgeon.

II. Situational prophylaxis - indicated for patients with infrequent, non-life-threatening attacks of hereditary angioedema (typically prior to various surgical procedures): fresh frozen plasma; ε-aminocaproic acid; tranexamic acid (due to the risk of thrombotic complications); oxymetholone - 2.5 - 5.0 mg daily for 7 days; danazol - 200 mg 3 times daily for 7 days.

III. Permanent prophylaxis. Patients are prescribed danazol (danol) at an initial dose of 600 mg daily. Once clinical remission is achieved, the patient is maintained on 200 mg daily continuously. Methyltestosterone at 0.01 g daily can be used as an alternative to danazol. After achieving clinical remission, the dose is reduced to 0.005-0.0075 g daily.

For patients with hereditary angioedema in whom danazol and methyltestosterone are contraindicated, administration of ε-ACA at 4 - 12 g daily per os or tranexamic acid at 1 - 1.5 g daily is recommended, under the monitoring of the blood coagulation system.

Prior to surgery, intravenous drip infusion is indicated with native plasma in an amount of 250-300 ml, ε-ACA 200 ml of a 5% solution, and dexazone 8-12 mg (prednisolone 90-120 mg).

Patients are subject to ongoing dispensary follow-up in order to monitor drug therapy, perform prophylactic measures prior to surgical procedures, tooth extractions, endoscopic examinations, etc., and monitor the blood coagulation system in patients receiving ε-ACA or tranexamic acid.

Currently, there is only one effective drug for preventing exacerbations and maintaining stable remission in hereditary angioedema - danazol (danol), which is prescribed at an initial daily dose of 600 mg. Once clinical remission is achieved, the dose is reduced to a maintenance dose of 200 mg daily.

As an example of the immune response in hereditary C1 inhibitor deficiency, we present the medical history of patient P., aged 20 (Table 68), who suffers from hereditary C1 inhibitor deficiency (hereditary angioedema) and was under observation at the municipal pediatric immunology center.

Patient P., aged 20, complains of recurrent edema in the facial area, Tongue, and Lips that began in childhood and has persisted throughout life. Examination reveals localized edema of the skin and subcutaneous tissue of the upper and lower lips, and the tongue. Similar episodes of edema are observed in the patient's father and paternal grandmother.

Diagnosis: hereditary C1 inhibitor deficiency (hereditary angioedema involving the lips and tongue).

Table 68. Immunogram of patient P., aged 20

Parameter		Result		Normal range
Hemoglobin		140		F - 115 - 145, M - 132 - 164 g/L
Erythrocytes		4.8		F - 3.7 - 4.7, M - 4.0 - 5.1x1012 /L
Platelets		280		150 - 320x109/L
ESR		14		2 - 15 mm/h
Leukocytes		73		4 - 9x109 /L
Neutr.	Band	Seg.	Eosin.	Baso.	Mono.	Lymph.	LGL	Plasm.
43 - 71 %	1 - 4 %		0.5 - 5%	0 - 1%	3 - 9%	25 - 37%	1-5%	0 - 1%
2000-6500	80-400		80-370	20-80	90-720	1600-3000	80-500	20-80
67	1	66	4	1	3	33	0	0
4890	70	4820	290	70	220	2410
Immunological parameters		Result	Normal	Immunological parameters			Result	Normal
Immunological parameters		Result	(SI Units)	Immunological parameters			Result	(SI Units)
T-lymph.	%	65	50 - 80	Ig G			15.5	8.0-18.0
CD-3	Abs. count	1566	1000-2200	Ig G				g/L
T-helper	%	39	33-46	Ig M			1.62	0.2-2.0 g/L
CD-4	Abs. count	939	309-1571	Ig M
T-suppr.	%	23	17-30	Ig A			2.7	0.3-3.0 g/L
CD-8	Abs. count	554	282-999	Ig A
IRI	CD-4/CD-8	1.69	1.4-2.0	CIC			26	30 - 50 Units
				CIC				opt. dens.
NK cells CD-16	%	19	12 - 23	Phagocytic		PI	78	60 - 80%
NK cells CD-16	Abs. count	458	72-543	activity		PNI	4.5	1.5 - 3.5
B-lymph.	%	12	17-31	NBT test		spon.	10	up to 10%
CD-22	Abs. count	390	109-532			ind.	24	_-
LST	spon.	9	up to 10%			res.	14	^h6%
	ind.	40	50-70%	Complement		CH-50	6	30 - 60
								hem. Units/mL

Immunogram Conclusion: primary immunodeficiency with complement system deficiency (C1 inhibitor activity is reduced).

Diagnosis: hereditary angioedema of the lips and tongue. Primary immunodeficiency with complement system deficiency (C1 inhibitor activity is reduced).

Treatment: ε-aminocaproic acid 100 ml of a 5% solution IV drip every 6 hours, followed by 1 g 4 times daily orally until the exacerbation completely resolves; furosemide 60 mg IV every other day.

Physiological Immunodeficiency of Early Childhood

It has been established that maternal malnutrition during intrauterine fetal development leads to impaired immune system development (primarily affecting the size and Functions of the Thymus), which can cause adverse health consequences for the individual postnatally and in adulthood.

During fetal development past 22 weeks of gestation, exposure to maternal food allergens can induce sensitization in the embryo, which may subsequently manifest as atopic reactions to that specific allergen.

During early postnatal maturation, the infant's immune system benefits from breast milk, which, in addition to essential nutrients, contains various Hormones that regulate the proper Development of the newborn's immune system. These include prolactin, among others. Many immunocompetent fetal cells express the prolactin receptor, which belongs to the IL-2 receptor family. The action of prolactin on cells bearing this receptor enhances the function of NK cells, promotes T-lymphocyte-dependent macrophage activation, facilitates lymphocyte maturation and functional enhancement, and modulates the differentiation of intraepithelial gamma-delta T lymphocytes.

A deficiency of Vitamins, mineral salts, Trace Elements, and antioxidants in the mother's diet during this period can lead to the development of immunodeficiency in the newborn.

During the post-weaning period, dietary exposure drives the polarization of type 1 and type 2 T-helper cell functions, promotes food tolerance, and lays the groundwork for atopic manifestations.

A list of clinical signs that raise suspicion of a primary immunodeficiency is provided in Table 50, and the CHARACTERISTICS OF THE main immunological manifestations of primary immunodeficiencies are presented in Table 51.

Last update: 13/08/2026

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