Lymphocyte Response Assay: A Window on Tissue Repair Capacity

Though it is most often thought of as the body’s defense department, the immune system also serves many important repair functions, identifying and neutralizing foreign substances and repairing the body’s tissues from daily wear and tear.

When healthy, the immune system is tolerant and foreign antigens are soaked up, neutralized, and recycled without burdening the body or provoking symptoms. Healthy people have a homeostatic rebalancing system that allows components of the immune system to process, recycle, and ultimately repair damaged tissues. Healthy immune tolerance is synonymous with homeostasis.

Unfortunately, tolerance and homeostatic rebalancing are reduced during illness, and are lost during prolonged chronic illnesses. When immune defense function is overburdened, the repair function is deferred. As these “repair deficits” accumulate, inflammation occurs, and when this becomes chronic, immune dysfunction and autoimmune conditions emerge.

We believe loss of tolerance and homeostasis accounts for most cardiovascular, chronic inflammatory and autoimmune conditions. These repair deficit conditions are major causes of increased morbidity and mortality while also increasing costs of associated care.

As integrative physicians, some of the toughest, most treatment-resistant conditions we manage are the autoimmune and inflammatory conditions resulting from loss of tolerance and deferred immune repair. Fortunately, we have a valuable tool that can help us get a better handle on these conditions.

A functional lymphocyte response assay (LRA) provides vital insights into immune system tolerance, ultimately improving our capacity to help patients with a wide variety of chronic disorders

Method Matters!

Identification of a patient’s unique immune reactivity should be fundamental to every comprehensive patient evaluation. There are many labs offering tests of immune hypersensitivity using a variety of different assays and particle count methods. The seemingly minor differences in testing methods may seem unimportant; however it is those methodological differences that are responsible for the vast difference in the clinical utility of the different tests.

In considering a test of immune responsiveness, begin with a distinction of the type of immune reaction covered by each test. Type 1 hypersensitivities (immediate allergies) are the histamine-amplified reactions with which people are most familiar. Immediate allergy tests like RAST serum assays or skin prick tests measure IgE. These are typically the only hypersensitivity tests used by conventional allergists.

Delayed or ‘occult’ hidden immune reactions are those in which symptoms occur hours to weeks after exposure. There are three mechanisms for delayed hypersensitivity reactions: Reactive antibodies (Type 2); immune complexes (Type 3), and direct T-cell responses (Type 4).

IgG Antibody Quantitation Tests: The most common tests of delayed hypersensitivity are the various antibody tests such as IgG, subclasses of IgG, IgA or IgM. These blood tests detect Type 2 (Reactive Antibody) reactions by measuring antibodies from B-lymphocytes and plasma cells.

IgG antibodies take months to appear and last a long time; in aggregate, they form the B cell aspect of immune memory. Some tests measure IgA or secretory IgA (sIgA). IgA antibodies reflect sensitization at mucosal surfaces or interfaces between inside and outside the body. Antibody tests provide information about presence and amount, but not function of antibodies to the tested item.

Antibody quantitation tests provide no information about the important Type 3 (Immune complex) or Type 4 (T Cell reactions). Immune complex reactions are associated with vasculitis, arthritis, and some liver or spleen dysfunctions. Type 4 (direct T Cell) responses are responsible for ~75% of delayed allergic reactions.

‘Particle Size’ Tests: These are often used to measure lymphocytes, and rely on devices to detect particles of a particular size, usually 10 microns or larger. Be aware that this can produce misleading results, since activated lymphocytes (memory white cells) are not the only type of cells with a typical size of 10 microns. Granulocyte debris, stacks of red cells (rouleaux), and platelet clumps can also be 10 microns. A recent published study reported a lack of reproducibility and questioned the validity of such particle counter techniques.

Lymphocyte Response Assays: More advanced reactivity testing includes functional procedures like ex vivo lymphocyte response assays (LRA) that concurrently measure all 3 delayed pathways. These tests measure harmful (symptom provoking) antibodies and T-cells, while avoiding false positives from the helpful, neutralizing antibodies that are not symptom-provoking. Standard IgG tests quantify these non-symptom provoking antibodies along with the more harmful IgGs, leading to a significant number of false-positive results.

Highly useful clinically in identifying causes of autoimmunity, LRA tests using the ELISA/ACT method are fast becoming the reference standard in delayed allergy measurements. The advanced LRA by ELISA/ACT is specific, sensitive and predictive for all three (Type 2, 3, and 4) delayed hypersensitivity pathways.

These specialized LRA tests are able to simultaneously measure all 3 pathways by employing an ex-vivo method of monitoring live lymphocytes as they are exposed to test antigens under simulated physiologic conditions. This method ensures that beneficial, neutralizing antibodies are not falsely identified as reactive.

The advanced ELISA/ACT method is an autologous cell culture with very low 3% day-to-day variance, with a false positive rate of under 0.1% and a false-negative rate of 1% false.

As a complete program, the LRA tests are combined with personalized assessment and interpretations focused on healthier habits and meeting individual nutrition needs. This has resulted in favorable community-based outcome studies in diabetes and fibromyalgia. We’ve also seen effective application of these tests across all autoimmune and inflammatory conditions over the three decades this procedure has been available for clinical use.

The LRA by ELISA/ACT is currently available only through ELISA/ACT Biotechnologies. The price of testing varies based on the number of items tested.

For simple, recent onset conditions, I usually recommend the smaller combination panels, which have 144 or 212 items. For complex, chronic multi-system conditions I recommend selecting from the more comprehensive panels consisting of 315- 500 items.

The lab does not accept insurance assignment but many patients successfully submit for reimbursement under CPT code 86353. Additional information about the test is available on the company’s web site at or by calling 1.800.553.5472.


Subscribe to Holistic Primary Care