Globulins IgA

Immunoglobulin A (IgA) is a crucial subclass of gamma globulins, also known as antibodies, which play a significant role in the body's immune defense, particularly at mucosal surfaces. 

Although IgG is the most abundant immunoglobulin in the bloodstream, IgA is predominantly synthesized daily and is the main antibody found in body secretions such as saliva, tears, respiratory and intestinal secretions, and breast milk. 

IgA exists in two forms: monomeric IgA in serum and dimeric secretory IgA (SIgA) in mucosal areas. SIgA, composed of two IgA molecules joined by a secretory component, is critical for protecting mucosal surfaces from pathogens by preventing their attachment and invasion, thus maintaining intestinal and respiratory health. 

Newborns receive maternal IgA through breast milk, providing essential immune protection until their own IgA production begins.

IgA is integral to mucosal immunity, where it neutralizes pathogens through mechanisms such as agglutination and immune exclusion. 

At mucosal surfaces, SIgA binds to antigens and bacterial cells, preventing them from colonizing and penetrating the epithelial barrier.  This aggregation limits bacterial motility and impacts bacterial physiology, aiding in pathogen clearance. 

SIgA also interacts with immune cells via Fc receptors, enhancing phagocytosis and immune response. 

By influencing host-microbial interactions and contributing to the stability of the mucosal environment, SIgA plays a vital role in both preventing infections and maintaining overall immune homeostasis.

Definition and Function of Globulin

What are Globulin Proteins, and What Do They Do in the Body?

Globulin proteins represent a diverse group of proteins found in the blood plasma and bodily fluids, playing essential roles in various physiological processes. Globulins are the second most abundant type of protein in the blood in humans, after albumin.  

Comprising several subclasses, including alpha, beta, and gamma globulins, they exhibit diverse structures and functions. 

Globulins are primarily synthesized in the liver and immune cells.  

Globulins are characterized using a laboratory technique called electrophoresis. In this process, a sample of blood plasma or serum is subjected to an electric field, causing the proteins within the sample to migrate based on their charge and size. 

Since globulins have varying charges and molecular weights, they migrate at different rates and form distinct bands on a gel or strip. These bands are then visualized and analyzed to identify and quantify the different types of globulins present in the sample. 

The three types of globulins determined by electrophoresis include:  [6.] 

Alpha Globulins: 

Alpha globulins are a group of plasma proteins that include transport proteins such as alpha-1 antitrypsin, which inhibits enzymes that degrade connective tissue, and haptoglobin, which binds free hemoglobin to prevent oxidative damage. 

Alpha globulins also contain lipoproteins involved in lipid transport, as well as acute-phase proteins like ceruloplasmin, which binds and transports copper ions. 

Overall, alpha globulins contribute to immune function, enzyme regulation, and lipid transport in the body.

Beta Globulins: 

Beta globulins comprise a heterogeneous group of plasma proteins with diverse functions. These proteins include transferrin, responsible for transporting iron ions in the blood, and complement proteins involved in the immune response against pathogens. 

Additionally, beta globulins encompass components of lipoproteins, such as low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), which transport cholesterol and triglycerides in the bloodstream. 

Beta globulins play critical roles in iron metabolism, immune defense, and lipid transport, among other functions.

Gamma Globulins: 

Gamma globulins, also known as immunoglobulins or antibodies, are key components of the immune system. 

These proteins are produced by plasma cells in response to specific antigens, functioning to recognize and neutralize pathogens such as bacteria, viruses, and toxins. 

Immunoglobulins consist of various classes, including IgG, IgA, IgM, IgD, and IgE, each with distinct roles in humoral immunity.  

IgG, the most abundant antibody class, provides long-term immunity against pathogens, while IgM serves as the primary antibody during the initial stages of infection. 

IgA plays a crucial role in mucosal immunity, while IgD and IgE are involved in antigen recognition and allergic responses, respectively. 

Gamma globulins are essential for mounting an effective immune response and maintaining immune homeostasis in the body.

What are IgA Globulins? 

IgA is one of the main classes of gamma globulins, or immunoglobulins (antibodies) produced by the body's immune system.  Although IgG is the most abundant immunoglobulin in the blood, more IgA is actually synthesized daily than any other antibody class.  [2.]

IgA comprises about 15% of the total immunoglobulins in the bloodstream, but it is also the predominant antibody found in various body secretions like saliva, tears, respiratory secretions, intestinal secretions, and breast milk.  [2.] 

There are two subclasses of IgA - IgA1 and IgA2 - which differ in their alpha heavy chain structures.  

Secretory IgA is dimeric, meaning it involves two IgA molecules joined together and associated with a special secretory component protein, enabling it to be transported across epithelial cell layers to mucosal surfaces and avoiding chemical digestion in the digestive system.  [11.] 

In contrast, monomeric IgA appears in the serum.  [11.] 

The primary role of IgA is to provide immune protection at mucosal sites like the respiratory and gastrointestinal tracts.  Newborn infants receive maternal IgA antibodies via breastmilk, helping protect their undeveloped gastrointestinal tracts before their own IgA production begins around 6 months of age.  [10.] 

IgA also activates the alternate pathway of complement.  [11.] 

Decreased or deficient IgA levels can occur in certain inherited immune deficiency disorders like selective IgA deficiency.  [22.] 

Overall, IgA globulins play a crucial role in mucosal immunity and immune defense at the body's mucosal surfaces and secretions by acting as the first line of antibodies against invading pathogens.  

IgA Globulin Role in the Immune System  [3., 7.]

Globulins IgA plays a crucial role in the immune system's defense against pathogens, particularly at mucosal surfaces. 

IgA’s Interactions with Pathogens

Secretory IgA neutralizes and eliminates pathogens through various mechanisms, including agglutination, neutralization, and triggering the IgA Fc receptor (FcαRI or CD89) on phagocytes. 

Various pathogens have evolved mechanisms to evade IgA-mediated clearance, indicating the significant protective capabilities of IgA at mucosal surfaces. 

It can interact with various bacterial and host proteins both through Fc receptors as described above and glycan regions, as well as through dedicated antigen-binding sites.

IgA’s Actions at Mucosal Surfaces

At mucosal surfaces, SIgA prevents pathogens from colonizing and invading mucosal surfaces by clumping antigens and bacterial cells together, a process referred to as immune exclusion. 

This aggregation can also limit bacterial motility and influence gene expression, thus impacting bacterial physiology.

SIgA-Mediated Clonal Aggregation

SIgA-mediated aggregation, particularly through a process called enchained growth, physically isolates bacterial clones, reducing their ability to spread and infect.  This aggregation aids in efficient clearance of pathogens from mucosal surfaces.

IgA’s Role in Host-Microbial Interactions

SIgA interacts with host factors and microbial components, playing a role in protecting against infections and potentially influencing microbial colonization and metabolism. 

The secretory component (SC) of SIgA also contributes to its stability and functionality in the mucosal environment.

Symptoms of Elevated IgA Levels

Symptoms of elevated IgA levels may vary depending on the cause of the IgA elevation, or the patient may be asymptomatic.  

For example, certain cancers such as multiple myeloma may cause symptoms including bone pain, unintentional weight loss, bone weakness and increased risk of fractures even with minor injuries.  [19.]

Liver disease, particularly alcoholic liver disease, is another possible cause of elevated IgA, and its pathogenesis is unrelated to multiple myeloma.  [4., 15.] 

Symptoms may include jaundice, fatigue and weakness, unintentional weight loss, abdominal pain and swelling, itchy skin, dark urine and pale stool, nausea and vomiting, easy bruising and bleeding, edema, and confusion.   

Back pain and changes in urination may also be seen due to IgA deposition in kidneys and resulting kidney damage.  [15.]

Infections or inflammation may be causes of elevated IgA levels, and symptoms depend on the nature and location of the infection or inflammation, as well as the individual’s ability to mount an immune response.  

Symptoms of Low IgA Levels

Symptoms of low IgA levels generally correlate with symptoms of decreased immunity.  

Symptoms may include:  [5., 9., 14., 17.] 

Increased susceptibility to infections, particularly:

• Ear infections, especially in young children 

• Colds 

• Sinus infections 

• Lung illnesses like bronchitis or pneumonia

• Gastrointestinal infections like giardiasis 

Gastrointestinal issues:

• Nodular lymphoid hyperplasia in the gastrointestinal tract 

• Increased risk of celiac disease 

• Dysbiosis and microbial imbalance in the gut

Autoimmune diseases:

• Higher prevalence of autoimmune diseases like type 1 diabetes 

Allergic symptoms in sensitized individuals:

• Low SIgA levels may increase allergic symptoms in sensitized individuals.

Lab Testing for Globulins IgA

Lab Test Information, Sample Collection and Preparation

Serum IgA levels are typically measured to assess systemic immune function, while secretory IgA levels in mucosal secretions, such as saliva or intestinal fluid from stool, provide information about mucosal immunity.

Blood testing requires a venipuncture.  Saliva or stool samples can be obtained from the comfort of home.  

It is important to consult with the ordering provider prior to sample collection, as special preparation may be required.  

Interpretation of IgA Lab Testing

Optimal Levels of IgA 

Optimal results of IgA will depend on sample type and the reference range of the lab company used.  It is important to consult with the laboratory company for their reference range.  

Optimal levels of IgA, whether in serum, stool, or saliva, are well within the reference range.  Elevated or decreased levels may signal inflammation, immune dysfunction or deficiency, or a pathological process.  

Blood Testing for Serum IgA Levels

Blood tests for serum IgA levels are generally done to assess for an excess or deficiency of IgA antibodies in the bloodstream.

Excess serum IgA levels are found in monoclonal IgA myeloma, respiratory and gastrointestinal infections, malabsorption due to some gastrointestinal conditions, liver disease, and some autoimmune conditions.  [8., 16., 18.] 

Decreased levels are often seen in selective IgA deficiency, ataxia telangiectasia, some autoimmune diseases, malabsorption in some patients, liver cirrhosis, Still’s disease, Waldenstrom's macroglobulinemia, and type III dysgammaglobulinemia.  [8., 16.]

Saliva Testing for IgA Levels

Salivary IgA (sIgA) serves as the first line of defense against pathogens in the oral cavity and upper respiratory tract.  Measuring sIgA levels can provide valuable insights into the mucosal immune response and oral immunity status.  [1., 21.] 

Salivary IgA levels can be altered in various physiological and pathological conditions such as inflammation, infections, stress, and medication use. 

Salivary IgA testing is particularly useful for detecting mucosal antibody responses, as evidenced by its poor correlation with serum IgA levels during SARS-CoV-2 infection.  [21.] 

This indicates that salivary IgA reflects an oral mucosal response, while salivary IgG responses are more predictive of systemic antibody levels, as measured in serum. 

Measuring salivary IgA can reveal mucosal exposure or infection even in the absence of systemic antibody responses, as demonstrated in unvaccinated children without confirmed SARS-CoV-2 infection showing evidence of exposure almost exclusively through specific IgA responses.  [21.] 

Low salivary IgA levels may indicate decreased immunity and/or agammaglobulinemia; it is also seen in ataxia-telangiectasia, and lower levels have been correlated with increased incidence of sinopulmonary infections.  [20.]

Stool Testing for IgA Levels

Stool testing for IgA levels describes immunity and microbial health of the gut.  

Elevated fecal IgA levels can indicate an increased immune response and inflammation in the gastrointestinal tract.  Studies have found that the concentrations of soluble IgA and IgG in the feces of patients with active inflammatory bowel disease (IBD) were significantly higher than those in healthy individuals.  [12.] 

Fecal IgA levels correlate positively with disease activity markers like C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Crohn's disease activity index (CDAI), and endoscopic scoring systems in IBD conditions such as Crohn's disease and ulcerative colitis. 

Low fecal IgA may also be clinically significant.  The key clinical significance based on these references is that low fecal IgA levels are associated with dysbiosis, reduced microbial diversity, impaired intestinal homeostasis, increased susceptibility to gastrointestinal infections and diseases (like IBD), and may also correlate with active IBD and disease activity markers.  [12., 13.] 

Testing fecal IgA can provide insights into mucosal immunity, gut microbiome regulation, and gastrointestinal health status.

The levels of fecal IgA and IgG were positively correlated with these markers and scoring systems in patients with Crohn's disease or ulcerative colitis, respectively.

Globulins IgA Related Biomarkers to Test

While Globulins IgA is a valuable biomarker, it is often useful to evaluate other related biomarkers in conjunction to gain a more comprehensive understanding of the immune system and disease processes.

Immunoglobulin G (IgG)

Immunoglobulin G (IgG) is the most abundant antibody class in serum and plays a crucial role in systemic immunity. 

Measuring IgG levels can provide insights into humoral immune function and complement the information obtained from IgA testing. 

Elevated IgG levels may indicate an ongoing immune response or certain autoimmune disorders, while decreased levels may suggest immunodeficiency.

Immunoglobulin M (IgM)

Immunoglobulin M (IgM) is the first antibody produced in response to an antigen and is primarily found in serum. IgM levels can be useful in assessing recent or acute immune responses, as well as certain autoimmune conditions like systemic lupus erythematosus (SLE).

Complement Proteins

The complement system is a crucial component of the innate immune system; measuring complement protein levels, such as C3 and C4, can provide valuable information about complement activation and immune dysregulation. 

Abnormal complement levels may be associated with various autoimmune disorders, infections, or inflammatory conditions.

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