Continuing Education Activity

Immunoglobulins (Ig) or antibodies are glycoproteins 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. The immunogen or antigen reacts with a B-cell receptor (BCR) on the cell surface of B lymphocytes. 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 a 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 that can quickly become plasma cells. In addition, circulating antibodies recognize antigens in tissue fluids and serum. This activity describes the physiology and pathophysiology of immunoglobulins.

Objectives:

• Describe the function of immunoglobulins.
• Outline disorders associated with immunoglobulin deficiencies.
• Summarize the presentation of patients with immunoglobulin deficiency.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance care delivery for patients with immunoglobulin deficiency.

Introduction

Immunoglobulins (Ig) or antibodies are glycoproteins produced by plasma cells. B cells are instructed by specific immunogens, for example, bacterial proteins, to differentiate into plasma cells. Plasma cells are protein-making cells participating in humoral immune responses against bacteria, viruses, fungi, parasites, cellular antigens, chemicals, and synthetic substances.[1] Immunoglobulins constitute about 20% of the protein in plasma.

The immunogen or antigen reacts with a B-cell receptor (BCR) on the cell surface of B lymphocytes. 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 a B cell makes an immunoglobulin (specificity). 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 that can quickly become plasma cells. Circulating antibodies recognize antigens in tissue fluids and serum.

The following are five types of immunoglobulins in humans:

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

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 containing 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. The hypervariable regions (HRR) contain the antigen-binding sites. There are three HRRs in the V domains of each light and heavy chain. These fold into regions that produce two antigen-binding sites at the tip of each monomer. All antibodies exhibit one or more functions (bifunctional), including activation of the complement system, opsonization of microbes to be easily phagocytosed, prevention of attachment of the microbes to mucosal surfaces, and neutralization of toxins and viruses.[1]

Immunoglobulin M

IgM has a molecular weight of 970 Kd and an 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).[3]

Immunoglobulin G

IgG is a monomer with an approximate molecular weight of 146 Kd and a serum concentration of 9.0 mg/mL. IgG is said to be divalent, i.e., it has two identical antigen-binding sites that comprise 2 L chains and 2 H chains joined by disulfide bonds. IgG 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. IgG1 is around 65% of the total IgG. IgG2 forms an important host defense against bacteria that are encapsulated. IgG is the only immunoglobulin that crosses the placenta as its Fc portion binds to the receptors present on the surface of the placenta, protecting the neonate from infectious diseases.[4] IgG is thus the most abundant antibody present in newborns.

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. IgA is the major antibody in secretions found in saliva, tears, colostrum, intestinal, genital tract, and respiratory secretions.

It appears in mucosa membranes as a dimer (with a J chain when secreted) and protects the epithelial surfaces of the digestive, respiratory,  and genitourinary systems. IgA possesses a secretory component that prevents its enzymatic digestion. It activates the alternative pathway of activation of the complement system.[5]

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 binds to high-affinity receptors on mast cells and basophils, causing allergic reactions.[6][7][8] IgE is considered the most important host defense against different parasitic infections, including Strongyloides stercoralis, Trichinella spiralis, Ascaris lumbricoides, and hookworms Necator americanus and Ancylostoma duodenale.

Immunoglobulin D

IgD is a monomer with a molecular weight of 184 Kd. IgD 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.[9] IgD may play an essential role in antigen-triggered lymphocyte differentiation.[2]

Receptors for Immunoglobulins

Immunoglobulins should interact with receptors to fulfill various biological functions 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.[10]

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. B cells regulate cell activation in the presence of a high titer of antibodies.
3. Fc gamma RIII (CD16) has two types. Fc gamma RIIIa is expressed on macrophages, NK cells, and some T cells. Fc gamma RIIIb is expressed on granulocytes and has a low affinity for IgG.
4. Fc epsilon RI is a high-affinity IgE receptor 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 various 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.[11][12][13]

Issues of Concern

Common adverse drug reactions to immunoglobulin therapy include headaches, malaise, fever, chills, and lethargy. Serious adverse drug reactions include acute kidney injury, venous thrombosis, aseptic meningitis, hemolytic anemia, and TRALI(Transfusion-related acute lung injury).[14] Increased risk of anaphylaxis is seen in patients with IgA deficiency having common variable immunodeficiency (CVID).[15]

Clinical Significance

Immunoglobulins or antibodies are essential in protecting 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[16]:

• 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 risk for autoimmune diseases, atopy, and anaphylaxis to IgA-containing products.[17]

Another common problem is the transient hypogammaglobulinemia of infancy. During the first 3 to 5 months, the child is healthy but becomes sick because of a physiological deficit of immunoglobulins. This disease is characterized by recurrent bacterial infections, including pneumonia, meningitis, otitis, arthritis, and osteomyelitis. This problem diminishes once the child starts producing immunoglobulins.[18]

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 six 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.[19]

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.[20] 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.[21] The patients have an increased risk of autoimmune disease, bronchiectasis, lymphoma, and sinopulmonary infections.

Waldenstrom macroglobulinemia (WM)  lymphoplasmacytic lymphoma is associated with a monoclonal immunoglobulin M (IgM) protein. The presence of the monoclonal IgM protein results in hyperviscosity syndrome(IgM>4000 mg/dL) characterized by headache, the Raynaud phenomenon, and retinal hemorrhages.[22]

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:

Quantitative Serum Immunoglobulins (classes and subclasses)

• IgG
• IgM
• IgA
• IgE[16]

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 evaluates the production of antibodies against antigens after the infectious disease has occurred.

Detection of Isohemagglutinins (IgM)

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

Isohemagglutinins are IgM antibodies the immune system produces in response to bacterial antigens 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, multiple myeloma shows a monoclonal peak in the gamma region of the electrophoresis that is consistent with a monoclonal antibody.
• Rheumatoid factor is an IgM antibody against the IgG Fc region and is an important seromarker of rheumatoid arthritis (RA).[23]

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 can treat 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.[24][25][26][27] In addition, therapy with IVIg started within two weeks from onset hastens recovery in patients with Guillain-Barré syndrome (GBS).[28]

Other Issues

The role of Immunoglobulin D has not been clear. However, recent research suggests Secreted Immunoglobulin D improves mucosal homeostasis and immune system vigilance by providing myeloid cells such as basophils and mast cells with IgD antibodies reactive against mucosal antigens against pathogenic microorganisms. However, additional research is needed to understand the precise function of immunoglobulin D.[9]

In a study, distinct immunoglobulin patterns predicted the risk of developing post-acute COVID-19 syndrome(PACS). Researchers observed decreased IgM, unaltered IgG1, and decreased IgG3 in patients with PACS. In addition. Evaluation of changes in COVID-19 patients at primary infection, six-month, and one-year follow-up, indicated that these total serum Ig concentrations remained steady over time. In summary, patients with either low IgM or low IgG3 had an increased risk of acquiring PACS, whereas patients with both high IgM and high IgG3 were less likely to develop PACS.[29]

Enhancing Healthcare Team Outcomes

Managing patients with immunoglobulin deficiencies involves an interprofessional team that includes nurses, clinicians, and pharmacists. Many of these patients are prone to infections and opportunistic organisms; hence surveillance and close monitoring of the patient is vital. Immunologists, transplant specialists, geneticists, and hematologists from  NIH collaborate in an interprofessional manner for the Blood and Immune Deficiency–Cellular Therapy Program (BID–CTP). These clinicians deliver state-of-the-art and experimental care to patients with rare blood and immune system diseases through an integrated and interprofessional approach to evaluating, treating, and monitoring patients.

Similarly, PIDTC (Primary Immune Deficiency Treatment Consortium)  is a network of 33 centers in North America that explore the management of severe primary immunodeficiency diseases (PID). PIDTC evaluates the natural history of patients treated for Severe Combined Immunodeficiency (SCID), Wiskott-Aldrich Syndrome, and Chronic Granulomatous Disease through retrospective, prospective and cross-sectional studies. In addition, the PIDTC has interprofessional collaborative partnerships with European and international colleagues and works with patient advocacy groups to promote community awareness.[30]

Nursing, Allied Health, and Interprofessional Team Interventions

Clinical nurse specialists (CNS) interventions and other healthcare professionals can reduce the risk of adverse events associated with immunoglobulin therapy. Providing adequate hydration before IVIG administration can reduce the risk of developing an acute kidney injury. Nursing interventions for post-infusion headaches are to decrease the infusion rate, and administering premedication with NSAIDs /acetaminophen can be helpful.[31] If there is a concern regarding the development of aseptic meningitis, the concerned clinician should be contacted immediately, and switching to subcutaneous immunoglobulin (SCIg) is required.[32]

Nursing, Allied Health, and Interprofessional Team Monitoring

Hypotension and anaphylaxis are known complications of immunoglobulin therapy. Hence, healthcare providers should monitor vital signs, shortness of breath, and urticaria. Transfusion-related acute lung injury (TRALI) can occur within six hours of transfusion. Monitor for clinical signs and symptoms such as hypotension, vomiting,  dyspnea, and hypoxemia, as TRALI requires immediate workup, cessation of infusion, and supportive treatment with close monitoring.[14]