Primary Immunodeficiencies Flashcards
X-Linked (Bruton’s) Agammaglobulinemia
- X-linked (Male. Female are carriers.)
- Autoimmune diseases: **Arthritis
Blocked B cell maturation beyond pre-B cell stage.
*Mutated Btk (Bruton’s Tyrosine Kinase) @ X chromosome
Btk is activated by pre-B cell receptor and signals B cell maturation
- Decreased/Absent Mature B cells in circulation
- Decreased Serum Ig
- Defective B cell immunity
Small germinal centers of lymph nodes.
May not become apparent until age 6 months when maternal immunoglobulins are depleted in breast milk
Most cases: Recurrent bacterial infections: Respiratory:
(Acute and Chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia)
–Haemophilus influenzae,
–Streptococcus pneumoniae,
– Staphylococcus aureus
–> Are almost always the causative organisms.
They are normally opsonized by Antibodies and cleared by Phagocytosis.
Viral infections, especially Enteroviruses (Echovirus, Poliovirus, Coxsackievirus).
Giardia lamblia (intestinal protozoan) --is normally resisted by secreted IgA but can cause persistent infections for them.
In general, however, most intracellular viral, fungal, and protozoal infections are handled well by the intact T cell-mediated immunity.
Common Variable Immunodeficiency (CVID)
Characterized by
1) *Poor antibody responses to infections
2) *Reduced IgG, IgA, and IgM serum levels
=> *Defects of B cell Maturation and Activation
- General decrease of Ig,
- More often IgG and IgA, sometimes only IgG
Clinical Presentation:
–Onset in Childhood or Adolescence
1) Recurrent Bacterial infections:
- -Sinusitis
- -Bronchitis
- -Pneumonia
- -Bronchiectasis
- -Otitis
Bordetella pertussis common in childhood.
2) *Viral infections:
- -(Herpes simplex or zoster)
- -Giardiasis (G. lamblia) ==> Persistent Diarrhea
3) *Autoimmune disease
4) *Lymphomas
–Both Hodgkins and **Non-Hodgkin’s Lymphomas are frequently associated
Lymphadenopathy, GI lymphoid hyperplasia, and splenomegaly are seen often
½ CVID cases are diagnosed before age 21; in some, complications don’t develop until adolescence or adulthood.
Normal Circulating B cells (2/3 cases)
- Grossly Normal Thymus and Lymph Nodes
- Hyperplastic Germinal Centers (increased B cells)
Some patients have mutations in genes encoding B cell growth factor receptors or costimulators of B and T cell interactions
Clinical: Caused by antibody deficiency; thus, resemble X-linked agammaglobulinemia.
Recurrent pyogenic (cause purulent inflammation) bacterial infections
Common to all patients is hypogammaglobulinemia, generally affecting all the Ig classes, but sometimes only IgG.
Normal or near-normal B cells in blood and lymphoid tissues. However, they cannot differentiate into Plasma cells. Hyperplastic follicles (probably due to defective regulation; B cells can proliferate in response to antigen but do not produce antibodies; thus, lack of normal feedback inhibition by IgG)
Heterogeous group of disorders, so both sporadic and inherited forms occur. Relatives of patients with familial forms have high incidence of selective IgA deficiency.
IgA Deficiency
Non-detectable IgA secretory and serum
- Genetic defect is unknown
- Virtual lack of *Circulating and *Secretory IgA, or may have *Partial IgA deficiency
Due to impaired differentiation of Naïve B cells to IgA-producing cells.
1) *Sprue-like (celiac disease-like) *Malabsorption Syndrome (Diarrhea) and
2) *Atopy (hyper-allergic), such as *Asthma, can be present
3) *Concomitant Autoimmune diseases:
– *Systemic Lupus
– *Rheumatoid arthritis
Predominant infections are
1) GI (diarrhea, giardiasis), and
2) Respiratory (bronchitis, sinusitis, pneumonias).
–Though may also see Urinary Tract Infections
Blood Transfusion causes Anaphylactic Shock
– Because are allergic to IgA because body does not recognize it as self because body does not make IgA.
Normal Gross and Microscopic Lymphoid Organs
Some patients may go on to Develop Common Variable Immunodeficiency (CVID), suggesting similar defect in B cell Maturation and Function.
Hyper IgM Syndrome
X-Linked
1) *IgM remains the Major Serum Ig
= *Defective B cell Heavy Chain Isotype Switch
2) *Also Severe Deficiency of Cell-Mediated Immunity
= *Due to Mutations in the CD40 Ligand gene
IgM can activate complement, but IgG is better
–Thus, –> Bacterial infections
CD40L on CD4+ Helper T cells binds CD40 on B cells and Macrophages,
· Mediating T cell-Dependent Activation
of B cells and Macrophages
· Defective T cell-Dependent B cell response interferes with Isotype switching.
· Recall that CD40L-CD40 interaction is what causes Isotype switching.
Recurrent pyogoenic infections because lack of opsonizing IgG.
Susceptible to pneumonia caused by the intracellular organism Pneumocystis jiroveci, due to the defect in cell-mediated immunity.
DiGeorge Syndrome
(Block in T cell Maturation)
Due to *Incomplete Development of
Thymus and Parathyroid
1) *Hypocalcemia (Low Ca2+)
2) *Tetany
3) *Cardiopathy
4) *Improves with Age
–Because a small amount of Thymus is present and is able to support T cell maturation, requiring a longer time.
Most frequent form of selective T cell maturation defect; they are all rare.
o Susceptible to certain viral, fungal, and protozoal infections, e.g. Respiratory Syncytial Virus, Aspergillus, Pneumocystis carinii.
Bare Lymphocyte Syndrome
Caused by *Failure to Express Class II MHC
Due to Mutations in Genes encoding Transcription Factor that induces Class 2 MHC Expression
*Profound Decrease in CD4+ Helper T cells
–Due to Defective Maturation in Thymus and Defective Activation in Peripheral Lymphoid Organs.
Very rare.
Affects Both Helper T cells help CTLs and B cells, so may see Both Intracellular and Extracellular infections.
Certain Rare Defects in T cell Activation
Due to
1) *Mutations in T cell Signaling Transducers
2) or *Cytokine Receptors Mediating Activation
Defects in T cell Activation Result in
1) Impaired Cell-Mediated Immunity and
2) Impaired T cell-Dependent Antibody Responses
*Often clinically indistinguishable from SCID
Defects in Leukocyte Adhesion
Innate Immunity Defects
Due to *Gene Mutations required for Expression of *Integrins or *Ligands for *Selectins
1) Blood Leukocytes Fail to Adhere Firmly to Vascular Endothelium and
2) Fail to Be Recruited Normally at Sites of Infection
Defects in Complement Proteins
Innate Immunity Defects
Cases described for almost every complement component and many complement regulatory proteins (inhibitors)
1) *C3 Deficiency Results in Severe, usually Fatal, Infections
2) Deficiencies of C2 and C4 Result in Immune-Complex Diseases Resembling Lupus, Instead of Immunodeficiency.
–*The fact that this doesn’t predispose to infections suggests that the Alternative Pathway may be Adequate for Host Defense.
3) *Similarly, Deficiencies of Complement Regulatory Proteins Lead to
1) Excessive Complement Activation and
2) Immune-Complex Diseases, but Not to Immunodeficiency.
Chronic Granulomatous Disease
Defect in *Innate immunity
Due to *Phagocyte Oxidase Gene Mutations
= Enzyme that Catalyzes ROS for Macrophages and Neutrophils
1) *Phagocytes are Unable to Kill Ingested Microbes
2) –So they Compensate by Recruiting Additional Macrophages and Lymphocytes, Forming *Granulomas
Diagnosis:
–*Negative result on *Nitroblue Tetrazolium Reduction Test
–Children with *Catalase-Positive Bacterial Infections (S. aureus, E. coli, Aspergillus)
Chediak-Higashi Syndrome
Innate Immunity Defect
Due to *Defective Leukocyte Lysosomal Granules, which do not function normally
–Blocked proper Fusion of the Phagosome and Lysosome together
1) *Affects Phagocytes (Macrophages and Neutrophils) and NK cells
2) –Resulting in Increased Susceptibility to Bacterial infections
3) *Mutations of Toll-like receptors (TLR) or defective Toll signaling also occur in Rare patients
Wiskott-Aldrich Syndrome (WAS)
*X-Linked
Onset in Early Childhood
- Caused by Mutations in genes of various
- Cytoskeleton Adapter Molecules of Hematopoietic cells,
–Resulting in Small, Dysfunctional Platelets and Leukocytes
1) *Recurrent Bacterial infections,
- -esp. *Encapsulated bacteria, e.g. Streptococcus pneumoniae
2) –Leading to *Pneumonia, *Meningitis, and *Septicemia
3) Later, Failure of T cell function predisposes to
- - Recurrent Herpes (Herpetic) infections and
- -*Pneumocystis Jirovecii Pneumonia
4) *Thrombocytopenia
- -With Normal number of Megakaryocytes in Bone Marrow (Bleeding Diathesis)
5) *Eczema
Gross: Normal Thymus and Lymph nodes
Microscopically:
- -T cell Depletion in Paracortical areas and
- -Decreased Serum T cells
Ataxia-Telangiectasia (AT)
*Symptoms Begin:
9 months – 2 years of age
Caused by *Abnormal DNA Repair
- -Which Interferes with the Normal Recombination of Ag Receptor Genes
- -and Leads to
- Defective Lymphocyte Maturation
==> Triad:
1) Progressive *Cerebellar Ataxia,
2) *Mucocutaneous Telangiectasias,
3) *Recurrent Respiratory Bacterial and Fungal infections
4) Leading to
* Bronchiectasis and *Pulmonary Fibrosis
*Defective DNA Repair
Increases *Risk of Cancer:
–mostly *Leukemias and *B cell Lymphomas
–But there is also increased risk for solid tumors.
Ig deficiency,
- -Particularly IgA and/or IgE
- -Serum IgM is usually elevated
Gross: Thymic Atrophy with Lymphocyte Depletion
–and Absent Hassall’s Corpuscles
Microscopically:
–Lymph Node T cell Depletion in Paracortical Areas and Mantle Zones
Treatment of Congenital Immunodeficiencies
Treatment varies with disease
Selective *B cell Defects can be treated with *Pooled Ig from *Healthy donors, providing Passive Immunity.
- SCID is *Fatal in early life unless the patient’s immune system is restored.
- Bone marrow transplant
- -The most widely used treatment
Ultimate goal is *Gene Therapy
Severe Combined Immunodeficiency (SCID)
The “50%” disease
- 50% are X-linked
- -Affecting Only Males
- -Females are Carriers
- 50% are Autosomal
- -Affecting Both Males and Females
The specific *genetic defect is Unknown in 50% of both X-Linked or Autosomal cases
Both B and T cell Abnormalities.
Susceptible to recurrent severe infections by wide range of pathogens, e.g. Candida albicans. P. jiroveci, Pseudomonas, Cytomegalovirus, Varicella, and a whole host of bacteria.
Die within First Year of Life Without Bone Marrow Transplantation.
- 1)Cytokine signaling subunit yc mutation
- 2)Adenosine Deaminase (ADA) mutation
- 3)Purine Nucleoside Phosphorylase (PNP) Mutation
- 4)Deficiency of a Kinase in the yc Receptor Signaling Pathway
- 5)RAG1 and RAG2 Gene Mutations
