Generales

By: Carlos Olimpo Restrepo S. - Journalist

Some diseases may be common in patients with comorbidities. However, some individuals do not have them and still develop infections caused by opportunistic microorganisms such as disseminated cryptococcosis. The Primary Immunodeficiency Group (GIDP), attached to UdeA's Faculty of Medicine, has studied these and other cases for almost four decades.

A large team of UdeA researchers works in the Primary Immunodeficiency Group laboratory in the university research headquarters (SIU). Photo: Communications Office / Alejandra Uribe Fernández

Imagine you have a security problem in your home and ask the authorities for help. When their agents arrive, they attack you instead of defending you from those threatening or harming you. In addition, other people passing by take advantage of the situation to attack you and do you more harm.

This partially explains in a graphic way how our defense or immune system works in some people with autoimmune diseases. It also helps to understand better why a fungus considered opportunistic caught the attention of the GIDP team of doctors and researchers attached to UdeA's Faculty.

In February 2014, Dr. José Luis Franco, coordinator of the GIDP, evaluated an adult patient in one of the city's fourth-level hospitals. The patient had been hospitalized for a month and a half for an infection called disseminated cryptococcosis, caused by the cryptococcus fungus. It had affected various parts of the patient's body. Her response to treatment had been partial despite being the proper treatment. The doctors at the hospital considered an acquired immunodeficiency such as HIV or even secondary, but the laboratory tests were negative. They even suspected a primary immune disorder, so they performed other tests to evaluate the immune system. They were all normal.  

Cryptococcus spp primarily infects individuals with a compromised immune system, such as those with HIV or undergoing immunosuppression after organ transplants to prevent rejection. Since the patient was HIV negative and had no other comorbidities, Franco suspected that she might have an autoimmune disease that had been described in the world's medical literature for years and was coined in 2021 as Adult Immunodeficiency, HIV negative. It is caused by autoantibodies - produced by the immune system itself - that suppress the anti-infective action of certain hormones or cytokines of the immune system. This favors infections spread by fungi, bacteria and viruses, among others. The problem was that the GIDP had no way of confirming this, as they did not have the technology to do so.

Study by many people and institutions  

Since 2013, José Luis Franco, PhD in basic biomedical sciences, and Andrés Augusto Arias, PhD in sciences from UdeA's School of Microbiology, among other GIDP doctors and researchers, have been working with colleagues from the Rockefeller University's Laboratory of Human Genetics of Infectious Diseases in the United States, the National Institute for Health and Medical Research (INSERM) in France, and UdeA groups to study the genetic and immunological bases of susceptibility to infections. Thus, it was possible to perform the tests that confirmed the definitive diagnosis for the patient mentioned above and two others detected by the infectious disease specialists who were part of the study.

GIDP's microbiologist Carlos Andrés Arango Franco focused his doctoral work on the study of these patients to confirm whether they had these autoantibodies that blocked a cytokine of the immune system, something previously unexplored in patients in Colombia. 

 "Seventy percent of people with cryptococcosis are HIV positive. Another percentage are those with other comorbidities - non-infectious diseases that facilitate infection - and a small proportion have no known risk factors. These are the patients we focus on," said the researcher. He pointed out that only about 60 of such cases have been described worldwide, and recently, three of them in Medellin.

And how did they detect them if they are so rare? "These people usually come to hospitals for emergencies, and doctors focus on treating the infection and order some tests, which will not find the real cause of this problem. Therefore, when we detect a suspicious case, we refer it to the GIDP," explained Isabel Cristina Ramírez. She is an internist, specialist in infectious diseases, professor, coordinator of the Specialization in Infectious Diseases of UdeA's Faculty of Medicine, and co-author of this work. 

In this regard, the GIDP coordinator added, "Sometimes it is difficult to put immunology into clinical practice because it is perceived as difficult to understand. As a result, a patient with an impaired immune system is sometimes undetected."

Thanks to GIDP's partnerships with the Institut Imagine, Carlos Andrés Arango conducted part of his research in Paris. Photo: courtesy Carlos Andrés Arango

Extensive research

Carlos Andrés did his master's degree with the GIPD on fungal infections in humans. Familiar with these patients, he set out to study them further during his PhD and traveled to the Institut Imagine in Paris, where he evaluated the presence of autoantibodies in the sera - a component of the blood - of these patients and the required functional tests. 

"Very likely, there are many more than the three we have found in this study, but it may be that not all physicians seek support from these specialized groups because they focus only on treating the patients for infection. That is why we have to encourage physicians to seek the GIDP if they have a suspicious patient," Dr. Ramirez emphasized.

Carlos Andrés commented that the study of patients at the GIDP is based on a fundamental hypothesis. "First, we argue that these individuals have this type of severe infection because they harbor deleterious or harmful genetic variants in their DNA which affect the development and function of the immune system. This condition leaves us without important defenses against invading microorganisms, as should normally be the case." These diseases, formerly known as primary immunodeficiencies (PI), are now called inborn errors of immunity (IEI) by the International Union of Immunological Societies. 

"When no obvious immune abnormalities are detected, and no harmful genetic variants are identified either, the hypothesis of autoimmune phenocopy is considered. It is a disease in which autoantibodies inhibit the function of cytokines and block, as in this case, the immune response to the fungus," as in the three patients in Arango's study.

The results of this research have a tremendous medical scope, as they reveal the genetic or autoimmune nature of susceptibility to infectious diseases in some patients. Understanding this is the first step in the lives of some waiting for answers about their condition. What is next? "Ideally, an appropriate treatment. For some, it could be antimicrobials for a longer period and in higher doses; for others, it could be replacement therapy for the missing component or modulation of the immune system so that it does not get out of control. For some patients, it could even be the replacement of the original affected immune system -a transplant- with that of a healthy compatible donor to reestablish the defenses," Dr. José Luis Franco said. 

He added that in cases in which a genetic variant is responsible for the disease, "the risk that other individuals in the family may eventually suffer from something similar can be established through genetic counseling. There is a path to definitive therapy for HIV-negative patients with adult immunodeficiency, and they should be permanently monitored to avoid relapses."

The research also calls on the medical community to embrace the knowledge of the immune system more. "This is like Pandora's box. We are detecting new molecular mechanisms and learning about new genes in cells that are important for controlling and eradicating fungi, bacteria and viruses that cause disease. Not only do we do our bit from the scientific point of view, but we also have a positive impact on the lives of our patients," said Carlos Andrés Arango.

A group with a social projection

A fundamental aspect for GIDP is the human and social impact on patients and their families. Access to effective modern and personalized treatments can mean a 180-degree turnaround in quality of life. The Group, some patients, and their families created the Diana García de Olarte Foundation for Primary Immunodeficiencies (Fundación Diana García de Olarte para las Inmunodeficiencias Primarias -FIP-) in 2006.

The GIDP has a set of specialized tests for immunological diagnosis offered by the Integrated Laboratory of Specialized Medicine (LIME). More than 30 tests are performed in this laboratory to evaluate the immune system in patients. In addition, the GIDP continues developing research projects to establish IEI's genetic, molecular and immunological bases. With the support of Minciencias, UdeA and foreign institutions such as the Rockefeller University and the Institut Imagine in Paris, it investigates the genetic and molecular bases that govern the immune response to the microorganisms that make us sick, such as the mycobacteria that cause tuberculosis. The Group's work goes hand in hand with the FIP, which financially and logistically supports access to diagnosis and treatment for patients with these diseases in Colombia.

Since the beginning of the pandemic, the GIDP has been working on COVID-19 in the international consortium Covid Human Genetics Effort (COVIDHGE), formed by research groups and universities from all over the world. The consortium has focused on revealing the genetic and immunological bases of susceptibility and resistance to this infectious disease in humans. It has contributed to the identification of known or novel genetic variants of susceptibility to SARS-CoV2, as well as the discovery of autoantibodies that block the activity of type-I interferons -proteins that help regulate the immune system- which are vital for the initial control of the infection. 

"Within the consortium, we knew this was possible, so we began to look not only at the cells and DNA of these people but also their serum. Autoantibodies were detected in many individuals," explained GIDP coordinator José Luis Franco Restrepo, who pointed out that this information could later be used to reduce the severe manifestations of COVID-19.

Members of the Primary Immunodeficiency Group. On the right is José Luis Franco, the coordinator of this team. Photo: courtesy of GIDP

A congress to address these problems

The First Colombian Congress on Inborn Errors of Immunity will be held in Medellin on August 11 and 12, 2023. The GIDP will host it, and renowned national and international speakers will attend it. 

Undergraduate and postgraduate students and specialists in the health area interested in attending can seek more information on the WhatsApp line 314 8646956 or download the QR on the FIP website.