6 Immunodeficiency disorders

IMP

Notes

Extra Objectives 01 02 03 Identify that Describe the difference is due to a Explain the presentations of classification of defect in the immune different types of Immuno- Immunodeficiency. function. deficiencies (e.g. recurrent ). 04 05 Understand the varieties of Know the laboratory immune system deficiencies investigations for involving defects in : immunodeficiency disorders - T cells, B cells, phagocytes and complement. Definition

A state in which the ability of the immune system to fight infectious disease is compromised or entirely absent *A person who has an immunodeficiency is called immuno-compromised

Immunodeficiency is considered to be present when infections are:

Frequent and severe

Caused by opportunistic microbes bacteria, viruses, fungi A boy with congenital ID lived in a bubble for 12 Resistant to antimicrobial therapy. ability of a microbe to resist years before he died the effects of medication The HIV virus is the only virus that attacks the immune system directly, while other viruses attack the immune system indirectly. Secondary (Acquired) Primary (Congenital)

●Malnutrition the body does not receive Genetic Mutation: ● enough nutrients for proper function Classification of Monogenic(Single gene)

● Immunodeficiency Viral and Bacterial Infections(aids) ● Polygenic (Multiple genes) ●Excessive Proteins Loss e.g (ID) (Burns, nephrotic syndrome) ●Immunosuppressive Therapy Distribution of Primary ●(Corticosteroids) Treatment that lowers the activity of the body's immune system *Antibody defects are more commonly seen

Acquired Immunity the effect Natural Immunity (adaptive) affected by secondary of (innate) affected by primary

primary ● T-cells and ● Phagocytic cells unable to ● B-cells secondary engulf or kill the antigen ● Complement proteins Pattern of infections and symptoms associated with primary immunodeficiencies

Disorder Opportunistic Other symptoms

Antibody Sinopulmonary (pyogenic bacteria), Autoimmune disease Gastrointestinal(enterovirus,giardia) (autoantibodies,inflammatory bowel disease)

Cell-mediated immunity N/A (pyogenic bacteria,pneumocystis carinii,virus) Gastrointestinal (viruses),mycoses of skin and mucous membranes(fungi)

Complement and other blood-borne Autoimmune disease(systemic lupus infection(streptococci,pneumococci,Neis erythematosus,glomerulonephritis) seria)

Phagocytosis Skin abscess, reticuloendothelial N/A infections(staphylcocci,enteric bacteria,fungi,mycobacteria)

Regulatory T cells N/A Autoimmune disease T-cell defects

DiGeorge Syndrome The most commonly and frequently seen abnormality. (Congenital Thymic Aplasia)

A congenital defect is characterized by: Low T-cell amounts

●Absence or underdevelopment of the Thymus gland (hypoplasia) the Thymus is where the T- cells mature (lecture 1) ● Hypoparathyroidism causes tetany which is involuntary muscles constriction, Ca affected (hypocalcemia) ● Facial abnormalities ● Cardiovascular abnormalities Features of DiGeorge syndrome: Management of DiGeorge syndrome: Fetal thymus tissue graft (14 weeks old) Extreme susceptibility graft: is the surgical transplant of living tissue to viral protozoal, and fungal *438 infections Profound depression susceptibility is lack of ability (decreased) of T-cell to resist some antigen numbers Absence of T-cell responses B-cell defects (Gammaglobulinaemias)

X-linked agammaglobulinemia(XLA) or patients with B-cell defects are subject to: Burton’s hypogammaglobulinemia

● the most common type (80%-90%) Recurrent bacterial infection BUT display normal ● (Congenital) marked by a defect in burton tyrosine kinase (BTK) which blocks immunity to most viral and fungal infections (Because maturation of B cells in the bone marrow the T cells are not affected. only B cells work in the case BTK is responsible for ● Reduces B-cell count to 0.1% (normal is 5%-15%) maturation of B cells into of bacterial infection and T cells work in cases of viral ● Absence of Immunoglobulins Plasma cells. infections) ● Affected Children Recurrent infections of pyogenic pus( producing) bacteria ● Management: Periodic IV Immunoglobulin injections B-cell defects are characterized by: - Complete absence of B cells or Plasma cells. X-linked hyper IgM syndrom - Low or absent of immunoglobulins ( Igs) or ● Congenital Selective absence of certain Igs. ● High Levels of IgM IgM can be High, normal or low (Variable) - ● Low levels of IgA, IgG, IgE (remember the word AGE) It’s genetically transmitted ( Autosomal recessive ) ● Management: Periodic IV Immunoglobulin injections ( X linked) making males show manifestation (express Because its X-linked, males are more affected Patients lack CD40-L (effect secondary) the disease) and females acting as normal carriers Selective immunoglobulin deficiency IgA( deficiency) ● (Congenital) It’s a deficiency in IgA (1:700) ● Asymptomatic (usually doesn’t cause symptoms) ● can show recurrent Respiratory tract infections (R.T.I) and GIT infections

● Management: Periodic IV Immunoglobulin injections Both T and B cell defects

Severe Combined Immunodeficiency almost complete absence of B&T cells functions (SCID) ● Congenital ● Causes Increased susceptibility to viral, bacterial, protozoal and fungal. (Because both T and B cells are affected) (starting at 3 months of age) ● Caused by enzyme deficiency: ○ ADA (Adenosine DeAminase) deficiency (important in DNA synthesis) 438 ○ PNP (Purine Phosphorylase) deficiency (important in detoxifying cell metabolites) ● Management: ○ Gene therapy ○ Infusion of purified enzymes ○ Bone marrow transplant

Leukocyte deficit Affects innate immunity

Quantitative defects Qualitative defects (Related to numbers) (related to function)

Congenital Agranulocytosis ●Defect in the gene inducing G-CSF Defects in Defects in Intracellular ( colony stimulating factor) killing important for producing (play a major role in bacterial infections) ●Features (can cause) : Leukocyte Adhesion Chronic Granulomatous Disease pneumonia and abscesses, Deficiency otitis media (ear infection) Defect in the adhesion (CGD) ● Defect in the oxidative complex responsible for molecules responsible for producing superoxide radicals leukocyte migration to sites of ● lack the “ infection (Rapid release of ROS) upon phagocytosis ● Characterized by recurrent life threatening bacterial and fungal infection and granuloma formation ● Repeated pyogenic infections and abscesses in multiple parts of the body

team438 Complement Deficiency (slightly edited) Deficiency in Components Definicey leads to:

C1 classical pathway C2 Immune-complex disease C4

Infection with pyogenic bacteria and Alternative pathway Factor D neisseria Spp. Factor B No immune-complex disease

MBL MASP 1 MB-lectin pathway Bacterial infections MASP 2 (mainly in childhood) C2 C4

Infection with pyogenic bacteria and C3 C3b deposition neisseria Spp.

sometimes immune-complex disease

Membrane attack complex C5 to C9 Infection with Neisseria Spp. Only components Laboratory diagnosis of Immunodeficiencies

● (CBC): Total & Differentiali nformation about cell count for each blood cell type

● Evaluation of Antibody Levels and response to antigens

● T and B cells count (Flow Cytometry)

● Measurement of Complement proteins and function (CH50)

● Assessment of Phagocytosis and respiratory burst (Oxygen Radicals) Take Home Messages:

Immunodeficiency may be congenital or acquired

it can involve any component of immune system such as cells, antibodies, complement etc. most common presentation of immunodeficiency is recurrent infection that may be fetal due to delay in diagnosis and lack of appropriate therapy Quiz

Question 1: Digeorge syndrome is a congenital defect that is marked by:

A - B-cell absence B- Hyperparathyroidism C- Bacterial infection D- none

Question 2:Burton’s hypogammaglobulinemia is marked by

A -Deficiency in ADA B-Deficiency in IgA C- High levels of IgM D- Defect in BTK

Question 3: Which of the following is caused by a defect in the gene inducing G-CSF

A -Congenital Agranulocytosis B- Leukocyte adhesion deficiency C- Chronic granulomatous disease D- A&C

Question 4: A deficiency in which of the followingmay lead to immune-complex disease

A - MB-lectin pathway B- C3b deposition C- Membrane attack complex components D- Alternative pathway

4: B 4:

3: A 3:

2: D 2:

D 1: team leaders

Hessah Fahad Alalyan

Faisal alotaibi ● Asma Alamri ● Abdulaziz alamri ● Fatimah Almeather ● Abdulaziz alrabiah ● Nourah Almasaad ● Hamad Almousa ● Renad AlOsaimi ● Homoud Algadheb ● Sara Alrashidi ● Mohammed albabtain ● Sarah Alqahtani ● Salih Alqarni ● Shatha Aldhohair ● Osama Mobeirek ● Yara Alzahrani

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