Immunoglobulin


Article Author:
Angel Justiz Vaillant


Article Editor:
Kamleshun Ramphul


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/18/2019 6:31:57 PM

Introduction

Immunoglobulins (Ig) or antibodies are glycoproteins that are produced by plasma cells. B cells are instructed by specific immunogens, for, example, bacterial proteins, to differentiate into plasma cells, which are protein-making cells that participate in humoral immune responses against bacteria, viruses, fungi, parasites, cellular antigens, chemicals, and synthetic substances.[1]

The immunogen or antigen reacts with a B-cell receptor (BCR) on the cell surface of B lymphocytes, and a signal is produced that directs the activation of transcription factors to stimulate the synthesis of antibodies, which are highly specific for the immunogen that stimulated the B cell. Furthermore, one clone of B cell makes an immunoglobulin (specificity). Besides, the immune system remembers the antigens that caused a previous reaction (memory) due to the development of memory B cells. These are intermediate, differentiated B cells with the capability to quickly become plasma cells. Circulating antibodies recognize antigen in tissue fluids and serum.

The following are 5 types of immunoglobulins in humans:

  1. IgM
  2. IgG
  3. IgA
  4. IgE
  5. IgD

Function

Basic immunoglobulin Structure and Function

Antibodies or immunoglobulins have two light chains and two heavy chains in a light-heavy-heavy-light structure arrangement. The heavy chains differ among classes. They have one Fc region that mediates biological functions (e.g., the binding capacity to cellular receptors) and a Fab region, where resides the antigen-binding sites. The chains are folded into regions called domains. There are 4 or 5 domains in the heavy chain, depending on their class, and two domains in the light chain. In the hypervariable regions (HRR) reside the antigen-binding sites. There are three HRR in the V domains of each light and heavy chain. These fold into regions that produce 2 antigen-binding sites at the tip of each monomer. All antibodies exhibit one or more functions (bifunctional) including activation of the complement system and neutralization.[1]

Immunoglobulin M

IgM has a molecular weight of 970 Kd and average serum concentration of 1.5 mg/ml. It is mainly produced in the primary immune response to infectious agents or antigens. It is a pentamer and activates the classical pathway of the complement system. IgM is regarded as a potent agglutinin (e.g., anti-A and anti-B isoagglutinin present in type B and type A blood respectively) and a monomer of IgM is used as a B cell receptor (BCR).[2]

Immunoglobulin G

IgG is a monomer with an approximate molecular weight of 146 Kd and a serum concentration of 9.0 mg/mL. It is synthesized mostly in the secondary immune response to pathogens. IgG can activate the classical pathway of the complement system, and it also is highly protective. The four subclasses of IgG include IgG1, IgG2, IgG3, and IgG4. IgG crosses the placentae, protecting the neonate from infectious diseases.

Immunoglobulin A

IgA appears in 2 different molecular structures: monomeric (serum) and dimeric structure (secretory). The serum IgA has a molecular weight of 160 Kd and a serum concentration of 3 mg/mL. Secretory IgA (sIgA) has a molecular weight of 385 Kd and a mean serum concentration of 0.05 mg/mL. It appears in mucosa membranes as a dimer (with J chain when secreted) and protects the epithelial surfaces of the respiratory, digestive, and genitourinary system. IgA possesses a secretory component that prevents its enzymatic digestion. It activates the alternative pathway of activation of the complement system.

Immunoglobulin E

IgE is a monomer. It has a molecular weight of 188 Kd and a serum concentration of 0.00005 mg/mL. It protects against parasites and also binds to high-affinity receptors on mast cells and basophils causing allergic reactions.[3]

Immunoglobulin D

IgD is a monomer with a molecular weight of 184 Kd. IgD that is present in a meager amount in the serum (0.03 mg/mL) and has an unknown function against pathogens. It is regarded as a BCR. IgD may play an essential role in antigen-triggered lymphocyte differentiation.

Receptors for Immunoglobulins

For immunoglobulins to fulfill various biological functions, they should interact with receptors that are mainly expressed on mononuclear cells, mast cells, neutrophils, natural killer cells, and eosinophils. Again, binding to these receptors is essential for immunoglobulin functions. It promotes several activities including phagocytosis of bacteria (opsonization); mast cell degranulation (as seen in type I hypersensitivity or allergic response); killing of tumors; and activation of antigen-presenting cells including macrophages and dendritic cells, which present antigens to T lymphocytes for the generation of cellular and humoral immune responses.[4]

The following are immunoglobulin receptors:

  1. Fc gamma RI (CD64) binds to monomeric IgG is expressed on phagocytes and is involved in the phagocytosis of immune complexes.
  2. Fc gamma RII (CD32) attaches to B-cells, monocyte/macrophages (phagocytes) and granulocytes. On B cells regulates cell activation in the presence of a high titer of antibodies.
  3. Fc gamma RIII (CD16) has 2 types. Fc gamma RIIIa is expressed on macrophages, NK cells, and some T cells. Fc gamma RIIIb is expressed on granulocytes and has low affinity for IgG.
  4. Fc epsilon RI is a high-affinity receptor for IgE that is shown on mast cells and basophils. It involves an allergic response.
  5. Fc epsilon RII  is expressed on leukocytes and lymphocytes and has homology with mannose-binding lectin.

Genetics of Immunoglobulins

The immune system can respond to many antigens by generating a vast diversity in immunoglobulins produced by plasma cells. V and J gene segments encode immunoglobulin light chains. The above genes, in addition to D gene segments, encode the heavy chains. The mechanisms that contribute to this great diversity of immunoglobulin specificities include somatic mutation (immunoglobulin heavy and light chain genes undergo structural modifications after antigen stimulation) and the presence of multiple V-region genes in the germline (antibody diversity also arises when numerous V genes are recombining with J and D segments). Gene conversion, recombinational inaccuracies, nucleotide addition, and assorted heavy and light chains also contribute to the diversity of immunoglobulin molecules.[5][6][7]

Clinical Significance

Immunoglobulins or antibodies play an essential role in the protection against bacteria, viruses, and fungi. When there is a deficiency of these glycoproteins, recurrent infectious diseases occur as seen in the following antibody deficiency disorders[8]:

  • X-linked agammaglobulinemia
  • Transient hypogammaglobulinemia of infancy
  • IgA deficiency
  • IgG subclass deficiency
  • Immunodeficiency with increased IgM
  • Common variable immunodeficiency

The most common immunodeficiency is Selective IgA deficiency, characterized by recurrent infections that affect the respiratory, digestive, and genitourinary systems. Recurrent pneumonia, Giardia lamblia infestation, and urinary sepsis are prevalent. The majority of patients can, however, be asymptomatic. They are at higher risks for autoimmune diseases, atopy, and anaphylaxis to IgA-containing products.[9]

Another common problem is the transient hypogammaglobulinemia of infancy. During the first 3 to 5 months the child is healthy, but he becomes sick because of a physiological deficit of immunoglobulins. This disease is characterized by recurrent bacterial infections including pneumonia, meningitis, otitis, arthritis, osteomyelitis, among others. This problem heals once the child starts producing immunoglobulins.[10]

X-linked agammaglobulinemia is also called Bruton agammaglobulinemia. It occurs due to a defect in Bruton Tyrosine Kinase (BTK) gene that prevents B-cell maturation. This condition is X-linked recessive and seen mostly in males. They present with recurrent bacterial and enteroviral infections after 6 months, once the maternal IgG is low. No B cells are seen in peripheral blood and immunoglobulins of all classes are absent. Patients also have absent or scanty lymph nodes and tonsils. Live vaccines are contraindicated.[11]

In common variable immunodeficiency (CVID), individuals acquire the immunodeficiency in the second or third decade of life or later. Both males and females can develop this problem. CVID may follow a viral infection, such as infectious mononucleosis. Giardia lamblia infestation and recurrent pyogenic infections characterize CVID. It may be due to a defect in B-cell differentiation. The patients have a risk of autoimmune disease, bronchiectasis, lymphoma, and sinopulmonary infections.

Laboratory Assessment of Immunoglobulins

The quantification of immunoglobulins and the study of their functions are vital for the immunodiagnosis of immunodeficiencies, autoimmunity, hypersensitivity reactions, and inflammatory disorders. The following examinations are routinely performed for the study of the behavior of antibodies[8]:

Quantitative serum immunoglobulins (classes and subclasses)

  • IgG
  • IgM
  • IgA
  • IgE

This assay is used to test for the presence of immunodeficiency disorders such as those in X-linked agammaglobulinemia. There are insufficient amounts of all classes of immunoglobulins, or they are absent. The presence of low IgA may be associated with recurrent diarrhea and lung and sinus infections. Low IgG is associated with pyogenic infections, and a high IgE may be found in parasitic infections.

IgG antibodies (post-immunization)

  • Tetanus toxoid
  • Diphtheria toxoid
  • Pneumococcal polysaccharide
  • Polio

This assay evaluates the quality of the immune response after vaccination. In healthy individuals, there is at least a 1:16 titer of antibody.

IgG antibodies (post-exposure)

  • Measles
  • Varicella Zoster

This test is to evaluate the production of antibody against antigens after the infectious disease has occurred.

Detection of isohemagglutinins (IgM)

  • Anti-type A blood
  • Anti-type B blood

Isohemagglutinins are IgM antibodies produced by the immune system in response to bacterial antigens present in the digestive system. It has been shown that their titers may be below 1:4 in antibody deficiency disorders.

Other assays

  • Test for heterophile antibody to measure the presence of antibodies against Epstein-Barr virus
  • Serum protein electrophoresis evaluates the level of antibodies qualitatively. For example, in multiple myeloma, it shows a monoclonal peak in the gamma region of the electrophoresis that is consistent with a monoclonal antibody.   

Clinical use of immunoglobulins

Immunoglobulins or antibodies can be used as a form of immunotherapy. Like drugs, they are prepared from a pool of blood donated at blood collection centers and processed through fractionation to separate the protein fraction from the cellular component. The purified immunoglobulin to some various degrees of purity can be used in the treatment of many immunological problems, including antibody deficiencies, severe combined immunodeficiency disorders (SCID), multiple sclerosis, myasthenia gravis, Kawasaki disease, systemic lupus erythematosus (SLE), organ transplantations, and many others.[12][13][14][15]

Enhancing Healthcare Team Outcomes

The managment of patients with immunoglobulin deficiences is with a multidisciplinary team that includes nurse. Many of these patients are prone to infections and opportunistic organisms, hence surveillance and close monitoring of the patient is vital.


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Immunoglobulin - Questions

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What determines immunoglobulin class?



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Which of the following determines the immunoglobulin class?



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Which class of antibody has the ability to cross the placenta?



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Which type of cells produce antibodies?



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Which of the following is the largest immunoglobulin in the body?



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Which of the following molecules is not within the immunoglobulin superfamily?



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Which is not a typical antibody molecule characteristic?



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Which of the following components determines the class-specific antigenicity of immunoglobulins?



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Immunoglobulin specificity resides in which of the following?



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Which one of the following immunoglobulins can be transferred from maternal to fetal circulation?



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Which of the following immunoglobulins can cause a hypersensitivity reaction in patients treated with IgG preparations?



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In an immunological test is needed to test the ability of certain antibodies to activate the classical pathway of the complement system. Which of the following immunoglobulins would be most effective for achieving this aim?



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A 65-year-old male presents with a femur fracture. He admits to pain and soreness in his thigh and a low-grade fever. Laboratory analysis shows an atypical monoclonal band in the serum protein electrophoresis. What is the most likely diagnosis?



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An in vitro experiment to down-regulate the synthesis of IgG and IgE is designed. Which of the following polyclonal antibodies (Ab) can be used for this purpose?



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A 21-year-old man presents to the clinician's office complaining of watery diarrhea for the last 3 months, nausea, bloating and a 5 kg weight loss. He went camping for a few days before the symptoms started. He has previously been prescribed some antibiotics that failed to improve his condition. Stool analysis reveals pear-shaped multi-flagellated organisms with 2 nuclei. Which of the following defense mechanisms might be impaired in this patient?



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An 11-month-old boy is brought to the hospital for recurrent pneumonia, otitis media, and diarrhea over the last three months. His cousin has passed away as a teenager with severe pneumonia, and his mother is worried that her son might be facing a similar problem. Stool analysis showed the presence of Giardia lamblia in his stool. Further analysis of this patient's serum showed decreased levels of IgA, IgM, IgG, and IgD. His T cell count is normal. If his lymph nodes are analyzed, which of the following structures might be abnormal?



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Immunoglobulin - References

References

Antibody: the flexible adaptor molecule., Burton DR,, Trends in biochemical sciences, 1990 Feb     [PubMed]
Vasilev N,Smales CM,Schillberg S,Fischer R,Schiermeyer A, Developments in the production of mucosal antibodies in plants. Biotechnology advances. 2016 Mar-Apr;     [PubMed]
Maurer M,Altrichter S,Schmetzer O,Scheffel J,Church MK,Metz M, Immunoglobulin E-Mediated Autoimmunity. Frontiers in immunology. 2018;     [PubMed]
Engels N,Wienands J, Memory control by the B cell antigen receptor. Immunological reviews. 2018 May;     [PubMed]
Wienands J,Engels N, Control of memory B cell responses by extrinsic and intrinsic mechanisms. Immunology letters. 2016 Oct;     [PubMed]
Justiz Vaillant AA,Ramphul K, Antibody Deficiency Disorder 2018 Jan;     [PubMed]
Stonebraker JS,Farrugia A,Gathmann B,Orange JS, Modeling primary immunodeficiency disease epidemiology and its treatment to estimate latent therapeutic demand for immunoglobulin. Journal of clinical immunology. 2014 Feb;     [PubMed]
Justiz Vaillant AA,Qurie A, Immunodeficiency 2018 Jan;     [PubMed]
Taneja A,Chhabra A, Bruton Agammaglobulinemia 2018 Jan;     [PubMed]
Vince N,Mouillot G,Malphettes M,Limou S,Boutboul D,Guignet A,Bertrand V,Pellet P,Gourraud PA,Debré P,Oksenhendler E,Théodorou I,Fieschi C, Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management. Human immunology. 2018 Jul;     [PubMed]
Ius F,Verboom M,Sommer W,Poyanmehr R,Knoefel AK,Salman J,Kuehn C,Avsar M,Siemeni T,Erdfelder C,Hallensleben M,Boethig D,Schwerk N,Mueller C,Welte T,Falk C,Haverich A,Tudorache I,Warnecke G, Preemptive treatment of early donor-specific antibodies with IgA- and IgM-enriched intravenous human immunoglobulins in lung transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018 Sep;     [PubMed]
Han AR,Lee SK, Immune modulation of i.v. immunoglobulin in women with reproductive failure. Reproductive medicine and biology. 2018 Apr;     [PubMed]
Farmakidis C,Pasnoor M,Dimachkie MM,Barohn RJ, Treatment of Myasthenia Gravis. Neurologic clinics. 2018 May;     [PubMed]
Lewis SM, Evolution of immunoglobulin and T-cell receptor gene assembly. Annals of the New York Academy of Sciences. 1999 May 18;     [PubMed]
Lewis SM,Wu GE, The origins of V(D)J recombination. Cell. 1997 Jan 24;     [PubMed]

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