COMMON VARIABLE IMMUNODEFICIENCY (CVID) Abdullatiff Sami Al-Rashed

Objectives

• What is Immunoglobulin (Ig)?

• CVID

• Hyper IgM Syndrome

What is Immunoglobulin (Ig)? Is a large Y-shaped protein

produced by B-cells that is used by the immune system to identify and neutralize foreign objects such as bacteria and viruses.

Antibody (or immunoglobulin) molecules are glycoproteins composed of one or more units, each containing four polypeptide chains: two identical heavy chains (H) and two identical light chains (L).

IgA antibodies protect body surfaces that are exposed to outside foreign substances.

IgA

They cause the body to react against foreign substances such as pollen, fungus spores, and animal dander.

IgE

are the largest antibody. They are found in blood and lymph fluid and are the first type of antibody made in response to an infection.

IgM

found in all body fluids. very important in fighting bacterial and viral infections they are the only type of antibody that can cross the placenta in a pregnant woman

IgG

found in small amounts in the tissues that line the belly or chest

IgD

There are 5 isotypes of Ig:

what is affinity maturation and isotype switching? • Isotype switching is a biological

mechanism that changes a B cell's production of antibody from one class to another, for example, from an isotype called IgM to an isotype called IgG.

• During this process, the constant region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same

• Since the variable region does not change, class switching does not affect antigen specificity.

• Affinity maturation ensures that repeated exposures to the same antigen will provoke greater antibody ligating affinity of the antibody secreted by successive generations of plasma cells.

Mechanism of class switch recombination that allows isotype switching in activated B cells

What is CVID?• Common variable immunodeficiency (CVID) is

a disorder that involves the following:

1. Low levels of most or all of the immunoglobulin (Ig)

classes,

2. A lack of B lymphocytes or plasma cells that are

capable of producing antibodies

3. Frequent bacterial infections.

• The World Health Organization (WHO)

recognizes more than 150 primary

immunodeficiency's ranging from relatively

common to quite rare.

Cont..

• CVID is shown to be a genetically determined primary immune defect.

• The result of these defects is that the patient doesn't produce sufficient antibodies in response to exposure to pathogens.

• As a result, the patient's immune system fails to protect them against common bacterial and viral (and occasionally parasitic and protozoan) infections.

Etiology of CVID The primary cause of common

variable immunodeficiency (CVID) remains unknown despite 40 years of research. Part of the problem is the heterogeneity of the disease.

Genetic factors may be involved. In approximately 20% of patients with CVID, a first-degree family member has a selective IgA deficiency. This finding may indicate that the genes are linked.

Further results reveal specific localization to the C4A gene and, rarely, to the C2 gene in the class III region of the major histocompatibility complex on chromosome 6.

Cont.. Studies on the cells of the immune system in

patients with CVID have revealed a spectrum of lymphocyte abnormalities.

Most patients appear to have normal numbers of B-lymphocytes, but they fail to undergo normal maturation into plasma cells capable of making the different types of immunoglobulins and antibodies.

Other patients lack enough function from helper T-lymphocytes necessary for a normal antibody response.

A third group of patients have excessive numbers of cytotoxic T-lymphocytes, although the role of these cells in the disease is unclear.

Pathophysiology of CVIDIntroduction:

• In patients with common variable immunodeficiency (CVID), numerous immune-system abnormalities are reported, the most common of which is defective antibody formation.

• Consequently, both humoral and cell-mediated lymphocytic responses are affected.

• Some CVID patients may have a defect in the T-cell ability to help B cells, and/or B-cell response to T-cell help.

Cont..1st : Changes in the humoral response:

The basic pathophysiologic process in CVID is a simple failure in the differentiation of B lymphocytes.

However, evidence shows that this defect in the pathway is not common among patients.

One study showed that, when B lymphocytes were stimulated with pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of normal T cells.

This finding suggests a defect in B-cell expression in surface molecules

Cont..2nd: Changes in the cell-mediated

response:

In 40% of patients with CVID, the CD40 ligand (which is expressed by activated CD4+ cells) is expressed in low levels on activated T cells.

In these patients, decreased IL-2 production after T-cell receptor stimulation is also present.

• A common defect is the response to antigens by CD4+ T lymphocytes.

Clinical features of CVID• Both males and females may have

CVID.

• Some patients have symptoms in the first few years of life while many patients may not develop symptoms until the second or third decade, or even later.

• The presenting features of most patients with CVID are recurrent infections involving the ears, sinuses, nose, bronchi and lungs.

• Patients with CVID may also develop enlarged lymph nodes in the neck, the chest or abdomen

Lymph node enlargement

Cont..• Signs and symptoms of

CVID include:

1. Hypogammaglobulinemia.2. Recurring infections involving the

ears, eyes, sinuses, nose, etc.3. Viral infections that usually

respond to antivirals.4. Enlarged lymph nodes.5. Fatigue.6. Abdominal pain, Bloating,

Nausea, Vomiting, Diarrhea, Weight loss.

7. And other not common clinical features

Child with hypogammaglobulinemia

Risk Factors Of CVID Most cases of CVID are classified as sporadic

and occur in people with no apparent history of the disorder in their family.

Although the cause of these cases is unclear, sporadic cases probably result from a complex interaction of environmental and genetic factors.

There are a few instances in which genetics may play a part in the development of the disease, and many doctors believe that in families in which more than one member has the illness, the risk of developing CVID is higher.

Investigation of CVID

Generally, serum

immunoglobulins are reduced,

Serum

hypogammaglobulinaemia is

the key finding present in all

patients with common variable

immunodeficiency (CVID), but

tests of immune function

should also be used.

Cont..The possible investigations can be

summarized as:

1.Laboratory studies:• FBC.• Autoantibody testing.• Serum electrophoresis.• Immunoelectrophoresis.• Radial immunodiffusion methods.• Immunoturbidimetric methods.• Assessment of antibody response.• Assessment of T and B lymphocytes by flow

cytometry.

Cont..2. Imaging: This is likely to be

required and may have to be extensive, including different modalities (CT scanning, MRI) according to the clinical manifestations of disease.

3. Further investigations:

such as pulmonary function tests, bronchoscopy, microbiological and histological testing, may be required to diagnose associated diseases.

bronchoscopy

CT scan machine

Diagnosis Of CVID The diagnosis is confirmed by

finding low levels of serum immunoglobulin, including IgG, IgA and usually IgM.

The number of T-lymphocytes may also be determined and their function tested in samples of blood.

With special laboratory techniques, it is possible to determine if B-lymphocytes produce antibody in a test tube (tissue culture) and if T-lymphocytes have normal functions.

Treatment of CVID Treatment usually consists of

immunoglobulin therapy, which is an injection of human antibodies harvested from plasma donations.

This can be given intravenously (IVIG) or subcutaneously.

This is not a cure, but it strengthens immunity by ensuring that the patient has "normal" levels of antibodies, which helps to prevent recurrent upper respiratory infections.

Prognosis of CVID The prognosis depends on the presence of severe

autoimmune disease, recurrent infections causing structural lung damage, and the development of a malignancy.

Other major factors in determining the prognosis is the extent of end-organ damage and the success of prophylaxis against future infections.

Epidemiology It is found in one per

50,000 to one per 200,000 with a reported incidence of one per 75,000 live births.

It affects male and females, and differing races equally.

Females have more switched memory B cells and tend to be diagnosed later and live longer.

Mode of Inheritance The common variable immune deficiencies can be

inherited in an autosomal dominant or autosomal recessive manner:

1. ICOS-associated, BAFFR-associated, and CD19-associated CVID are inherited in an autosomal recessive manner.

2. TACI-associated CVID is inherited in either an autosomal recessive or autosomal dominant manner, depending on the specific gene mutation involved and the penetrance of that allele in the affected family.

The cause and mode of inheritance are unknown in 75%-80% of individuals with CVID.

Hyper IgM Syndrome Hyper IgM syndrome is a family of genetic disorders in

which the level of Immunoglobulin M (IgM) antibodies is relatively high

Patients with Hyper IgM (HIM) syndrome have an inability to switch production of antibodies of the IgM type to antibodies of the IgG, IgA, or IgE type.

The hyper IgM syndrome results from a variety of genetic defects that affect this interaction between T-lymphocytes and B-lymphocytes.

The most common form of hyper IgM syndrome results from a defect or deficiency of a protein that is found on the surface of activated T-lymphocytes. The affected protein is called “CD40 ligand”

Cont..

The most common problem is an increased susceptibility to infection including recurrent upper and lower respiratory tract infections.

Regular treatment with immunoglobulin replacement therapy every 3 to 4 weeks is effective in decreasing the number of infections

References

http://www.ncbi.nlm.nih.gov/books/NBK1299/

http://emedicine.medscape.com/article/1051103-overview#a0104

http://ghr.nlm.nih.gov/condition/common-variable-immune-deficiency/

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