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Lecture
Immunodeficiencies
Definition
Immunodeficiency
The inability of the body to produce a sufficient
immune response.
Primary and Secondary
Immunodeficiencies
Primary deficiencies – inherited:
- inherited dysfunction of genes encoding
molecules important for correct immune functioning.
Secondary deficiencies – acquired:
- acquired damage of molecules and/or cells important for
correct immune functions caused by external or internal factors
Deficiencies involve: - cellular and humoral immunity
- Ag specific or non-specific mechanisms
Primary immune deficiences
1) Frequency: more frequent in men
2) Genetics: - point mutations, gene deletions
- linked with X chromosome
3) Consequences
- absence or dysfunction of a given molecule
Clinical manifestations
Clinical manifestations of immune deficiencies:
1) Increased susceptibility to infections
2) Autoimmune diseases
3) Lymphoproliferative diseases
4) Allergy
5) Without manifestations – replaced by other immune
mechanisms or manifested only under certain conditions
Deficiences of innate immunity
Deficiencies of Innate Immunity
Deficiencies of innate immunity involve:
- phagocytosis
- complement
- combined immunodeficiencies
Frequency: frequent, serious medicinal problem
Deficiences in Complement
Deficiences are rare.
1) Deficiency in C1, C2, C3 and C4 - immune complexes
- diseases like Lupus erythematodes
- pyogenic infections
2) Defeciency of C1 inhibitor (hereditary angioedema)
Deficiences in phagocytosis
Number of phagocytes
1. Kostmann syndrome
2. Cyclic neutropenia
3. Reticular dysgenesis
Deficiences in phagocytosis
Function of phagocytes
1. Chronic granulomatous disease (CGD)
defects in NADPH-oxidase, X linked
2. Leukocyte adhesion deficiency (LAD I, II)
LAD I > defect in CD18 molecule – diapedesis, without manifestations
LAD II > defect in ligands for selectins (sialyl-Lex antigen)
3. Reticular Dysgenesis
Deficiences of acquired immunity
Deficiencies of Specific Immunity
Deficiences of specific immunity involve:
- deficiencies of antibody production
- T cell dysfunction
- combined immunodeficiencies.
Antibody deficiencies I
- Failure of B cells and Ab production.
- Patients suffer from encapsulated microbes.
1) Agammaglobulinemia linked with X chromosome (Bruton)
- Mutation in protein kinase C (Btk) encoding signal transduction through BCR
- B cells and Ab of all classes totally absent in blood.
2) Selective immunoglobulin deficiencies (dysimmunoglobulinemia)
- Partial or total absence of some isotypes
- The most frequent is IgA deficiency. In mucosa, partially supplied by IgM,
in lower respiratory by IgG.
- Without manifestations or higher sensitivity to respiratory
infections, allergy, autoimmunity (and tumors?)
Antibody deficiencies II
3) Selective deficiency of IgG subclasses
Deficiency of IgG subclasses also in combination
with IgA deficiency
4) Selective deficiency of Ab specific for certain Ag
Deficiency of Ab against lipopolysaccharides
5) Transient hypogammaglobulinemia of infancy
Delayed onset of IgG production in newborns.
Spontaneous recovery.
Common variable immunodeficiency
( CVID )
Definition
Mixed group of diseases in which the production of antibodies is defective.
Increased risk of life-threatening infections.
CVID
COURSE
Clinically, CVID may resemble HIV infection, as it may cause
• weight loss
• swelling of the lymph nodes
• diarrhea
• lymphoma
• idiopathic thrombocytopenic purpura
CVID
Symptoms :
INFECTIONS
• Acute, recurring bacterial infections, including pneumonia,
bronchitis and sinusitis.
• infections from Hemophilus spp. , Streptococcus pneumoniae ,
herpes, GI-tract infections
• Children with CVID are susceptible to otitis media, and infections
may develop in the joints, bones, skin and parotid glands.
AUTOIMMUNITY
• Autoimmune diseases (autoimmune hemolytic anemia, idiopathic
thrombocytopenic purpura, rheumatoid arthritis, celiac disease)
CANCER increased risk cancer (non-Hodgkin lymphomas and
adenocarcinomas)
CVID
•Aethilogy
• homozygous null mutations in ICOS gene => panhypogammaglobulinemia
• a susceptibility locus exists in the class III MHC region
• Cause of CVID is uncertain and may vary among patients.
• in 10% of cases familiarity exists
CVID
Pathogenesis:
• Many patients with CVID have near-normal numbers of antibodybearing B cells, but these fail to mature into plasma B cells -> low
IgG, IgA and IgM (or undetectable amounts of the immunoglobulins).
• Other CVID patients have low numbers of B cells.
• Some have abnormalities of T-cells (ICOS gene).
CVID
Epidemiology:
• CVID is the most common clinically significant primary immunodeficiency
disease (several thousand patients)
• It occurs equally in both sexes.
• CVID may become apparent in infancy or as late as the 5th decade of life.
The average age of onset is 27 years.
CVID
Treatment
- prophylactic administration of human immunoglobulin every
3 weeks throughout the patient's life, along with
- systemic antibiotics as necessary for the management of
concomitant infections.
T cell immunodeficiences
Distinguished as:
• severe combined disorders - T cell totally absent
• diseases caused by functionally abnormal T cells
T cell immunodeficiences
Severe combined immunodeficiency
- The most serious primary deficiency
- Manifested early after delivery – viral infections, intracellular
microbes, opportunistic microbes
- Lethal without treatment
- Aethiology: heterogeneous, increasing number of diseases
T cell immunodeficiences
1. Adenosin deaminase deficiency
2. Severe Combined Immunodeficiency (SCID)
3. Reticular dysgenesis
Combined immunodeficiences
1. Ag presentation
6. Omen Syndrome
2. Activation of T cells
7. Hemophagocytic Lymphohistiocytosis
3. Hyper IgM syndrome
8. X-linked Lymphoproliferative Syndrome
4. Wiscott-Aldrich syndrome
9. Familiar Autoimmune Lymphoproliferative
Syndrome
5. Chediak – Higashi syndrome
Other Deficiences
Hyperimmunogamaglobulinemia (Job syndrome)
Mucocutaneous candidosis
Ataxia teleangiectasia
Secondary Immunodeficiences
Deficiences are caused by
1) Infections (HIV)
2) Metabolic disease (diabetes melitus, kidney and liver dysfunctions
3) Nutrition (proteins, vitamins, minerals)
4) Treatment procedures (splenectomy, chemotherapy...)
Autoimmunity
Immunopatologic reactions
Immune mechanisms recognize self antigens and destruct
self cells and molecules
Autoimmunity
Mechanisms (intrinsic factors):
1.) Association with certain MHC molecules >>> HLA-B27 -Bechterev disease
2) Deficiency in cytokines
3) Deficiency in genes which regulate apoptosis (Fas, FasL, Bcl-2)
4) Association with immunodeficiencies
5) Polymorphism of TCR genes and H chains of Immunoglobulines
6) Hormonal effects
Autoimmunity
Mechanisms (external factors):
Infections, stress, drugs, UV radiation
1) Cryptic Ag (intracellular)
2) expression of MHCII - inflammatory cytokines – presentation of Ag, which
are normally not accessible
3) :”Molecular mimicry” similarity of self and microbial antigens
4) Microbial superantigenes
Autoimmunity
Mechanisms (external factors):
Infections, stress, drugs, UV radiation
1) Cryptic Ag (intracellular)
2) expression of MHCII - inflammatory cytokines – presentation of Ag, which
are normally not accessible
3) :”Molecular mimicry” similarity of self and microbial antigens
4) Microbial superantigenes
Autoimmunity
Lupus erytematodes
Reumatoid artritis
Sjörgen disease
Systemic sclerodermitis
Connective tissue disease
Antiphospholipid disease
Vasculitis
Autoimmunity
Hashimoto thyroiditis
Graves-Basedow disease (TSH)
Diabetes melitus
Myasthenia gravis (acetylcholine receptors)
Hematological (cytopenias)
Skin autoimmune reactions